Recent Developments and Evolving Therapeutic Strategies in KMT2A-Rearranged Acute Leukemia.

Introduction

Histone‐lysine‐N‐methyltransferase‐rearranged ( KMT2A ‐r) acute leukemia, commonly known as mixed lineage leukemia ( MLL ), is a distinct subtype of acute leukemia marked by genetic abnormalities in the KMT2A gene (also known as ALL‐1, HRX , or HTRX ). In patients, both adult and pediatric, this disease has been linked to a poor prognosis [ 1 ]. Several studies have explored key aspects of KMT2A ‐r acute leukemia, including its genetic basis, clinical implications, and treatment options [ 2 , 3 , 4 , 5 ]. A specific genetic rearrangement occurs in KMT2A ‐r acute leukemia, most commonly represented by the translocation t(4;11)(q21;q23) [ 1 , 6 ]. This genetic alteration fuses the KMT2A gene with another gene, often the AF4 gene, creating a fusion protein that disrupts the normal function of KMT2A . This disruption leads to uncontrolled cell growth and the development of leukemia [ 7 , 8 ]. Regarding the clinical implications of this condition, KMT2A ‐r acute leukemia is linked to negative clinical outcomes. Individuals with this subtype often have a more aggressive disease course and a greater chance of relapse as compared to other kinds of leukemia [ 1 , 9 ]. It is more prevalent in infants and very young children, accounting for a significant portion of infant leukemia cases. This genetic abnormality is less common in adults but still challenging to treat [ 10 ].

KMT2A ‐r acute leukemia typically involves genetic testing to identify the specific KMT2A rearrangement. Different molecular techniques can be used to achieve this, such as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) [ 6 ]. Detecting this genetic alteration is crucial for both confirming the diagnosis and guiding treatment decisions. Managing KMT2A ‐r acute leukemia is complex and often requires intensive therapy. Standard treatment approaches may include chemotherapy, targeted therapies, supportive care, and transplanting stem cells. Researchers have recently investigated novel therapies, including epigenetic and immunotherapy approaches, to provide better outcomes for people suffering from this high‐risk subtype [ 11 ]. The prognosis for KMT2A ‐r acute leukemia remains challenging due to its aggressive nature. However, advancements in treatment and ongoing research are gradually improving survival rates and long‐term outcomes. Early detection and appropriate therapeutic interventions are key factors in increasing the chances of remission and long‐term survival for patients with KMT2A ‐r leukemia.

Considering the fact that KMT2A ‐r leukemia is a complex disease with evolving research, this review aims to synthesize and update our knowledge in this field, providing a comprehensive overview of the latest findings and understanding of the condition. We will explore the general characteristics, clinical presentations, and treatment options of KMT2A ‐r leukemia. This will contribute to understanding clinical implications, including diagnosis, prognosis, and treatment strategies, which is essential for healthcare professionals and researchers.

General Gene Characteristics and Associated Mechanisms

For proper hematopoiesis to occur, the KMT2A gene is essential. It regulates gene expression by modifying chromatin structure. In KMT2A ‐r acute leukemia, chromosomal rearrangements disrupt the KMT2A gene, leading to fusion with partner genes, including AF9, ENL, AF4 , AFF6, AF10, ELL , and KMT2A‐PTDS , which together are responsible for most KMT2A fusions [ 12 , 13 ]. In effect, the fusion of 11q23 with greater than 100 distinct partner genes occurs in KMT2A ‐r leukemias, resulting in various KMT2A fusion proteins. These highly complex fusion events can have different functional consequences [ 11 , 14 ]. The partner genes that fuse with the KMT2A gene vary in different cases of leukemia, and the specific fusion partner can impact the disease's characteristics and prognosis. Understanding these partner genes is crucial for studying the pathogenesis of KMT2A ‐r leukemias and developing targeted therapies.

The characteristic changes in the KMT2A gene are associated with several oncogenic mechanisms, including the generation of oncogenic fusion proteins, epigenetic dysregulation, homeobox A ( HOXA ) cluster gene activation, and aberrant self‐renewal, contributing to the poor prognosis and therapeutic challenges that characterize KMT2A ‐r acute leukemia. Combining KMT2A with partner genes creates oncogenic fusion proteins that have a disrupted KMT2A domain, impairing its normal regulatory functions [ 15 , 16 ]. Moreover, KMT2A ‐r leukemia is linked to profound epigenetic dysregulation, such as histone acetylation, histone methylation, and DNA methylation [ 17 ]. The fusion proteins affect the modification of histones and chromatin structure, leading to abnormal gene expression patterns [ 14 ]. This deregulation contributes to leukemia's development and provides targets for alternative strategies for leukemia treatment [ 17 , 18 ].

One of the key mechanisms of KMT2A ‐r acute leukemia involves the activation of HOXA cluster genes, particularly HOXA9 and MEIS1 [ 19 ] (Figure 1 ). The fusion proteins can increase these genes' expression, promoting leukemogenesis. Therefore, in KMT2A ‐r acute leukemia, downregulation of the HOXA and MEIS1 genes may decrease proliferation and hinder engraftment [ 20 ]. Since KMT2A ‐r acute myeloid leukemia ( KMT2A ‐r‐AML) is characterized by the overexpression of HOXA/MEIS1/PBX3 homeobox genes, tackling the interactions of MEIS1/PBX3 may offer a promising therapeutic approach for treating these AML subtypes [ 21 ]. Another key mechanism is attributed to KMT2A ‐r leukemias often exhibiting enhanced self‐renewal capacity, which allows leukemic cells to proliferate and evade normal regulatory mechanisms. For example, F‐box protein 22 (FBXO22) promotes KMT2A ‐r‐AML aberrant self‐renewal by enhancing the degradation of BACH1 (BTB domain and CNC homolog 1) [ 22 ]. Moreover, it has been demonstrated that FOXM1 (Forkhead Box M1), a known transcription factor that stimulates cell proliferation in a range of cancer cells, is necessary for the quiescence, self‐renewal, and survival of leukemia stem cells (LSCs) transformed by MLL‐AF9 in vivo. Mechanistically, elevated FOXM1 expression stimulates the Wnt/β‐catenin signaling pathways by attaching itself to the β‐catenin protein and preventing its breakdown., thereby preserving LSC quiescence and promoting LSC self‐renewal in KMT2A ‐r‐AML [ 23 ] (Figure 1 ). Studies such as these demonstrate how important these mechanisms are to KMT2A ‐r‐AML and present potential therapeutic targets for exploration.

KMT2A ‐Rearranged Acute Lymphoblastic Leukemia ( KMT2A ‐r‐ ALL )

Genetic rearrangements of KMT2A with partner genes, producing KMT2A fusion proteins and driving KMT2A ‐r acute lymphoblastic leukemia ( KMT2A ‐r‐ALL) [ 6 ]. More than 100 partner genes have been identified, with the most prevalent ones being AFF1 (formerly AF4 ; ∼56.5%), MLLT1 (previously ENL , ∼18.5%), and MLLT3 (previously AF9 ; ∼11.8%) [ 6 ]. KMT2A ‐r‐ALL is prevalent in newborns under 1 year old. A rare yet extremely aggressive form of juvenile leukemia known as KMT2A ‐r infant ALL ( KMT2A ‐r iALL) is known for its poor prognosis and challenging treatment [ 24 ]. It is associated with unfavorable clinical outcomes. The genetic landscape of KMT2A ‐r‐ALL is complex, with distinct somatic mutations and genetic alterations that contribute to the disease's aggressiveness [ 6 , 11 ].

Cytogenetics and Immunophenotype

KMT2A ‐r‐ALL, as a subtype of acute lymphoblastic leukemia, predominantly affects lymphoid cells. These cells, including B‐cells, NK cells, and T‐cells, become malignant and disrupt the production of normal lymphocytes, resulting in an increased production of immature lymphoid cells [ 9 ]. In KMT2A ‐r‐ALL, the karyotype often reveals either hyperdiploidy or hypodiploidy (Figure 2 ). These cytogenetic abnormalities are associated with the disease and can influence the prognosis [ 25 ]. KMT2A ‐r‐ALL typically exhibits a lymphoid immunophenotype. The leukemic cells express markers associated with lymphoid lineage differentiation, such as CD19, CD79a, and CD22 for B‐ALL, and CD7, CD2, and cytoplasm CD3 (cCD3) for T‐ALL (Figure 2 ). These markers are consistent with the B‐cell or T‐cell origin of the leukemia [ 26 ]. Unlike typical precursor B‐ or T‐cell ALL, KMT2A ‐r‐ALL often lacks expression of terminal deoxynucleotidyl transferase (TdT), a marker typically present in lymphoblasts. This loss of TdT expression can help differentiate KMT2A ‐r‐ALL from other subtypes of ALL [ 6 , 26 ]. It is essential to note that the specific partner gene involved in the KMT2A rearrangement can influence the immunophenotype and clinical features of KMT2A ‐r‐ALL. Therefore, a comprehensive evaluation of both cytogenetics and immunophenotype is crucial for diagnosis and risk stratification.

Risk Stratification and Clinical Presentation

KMT2A ‐r‐ALL is also aggressive and may occur more commonly in children. Patients with KMT2A ‐r‐ALL may present with symptoms related to the overproduction of lymphoid cells, including enlarged lymph nodes and spleen, and a higher chance of central nervous system involvement [ 9 ]. This necessitates careful monitoring and prophylactic treatment to prevent or manage CNS disease. In addition, patients often present with rapidly progressing symptoms, including fatigue, fever, bone pain, and bleeding tendencies. Some cases of KMT2A ‐r‐ALL may exhibit features of mixed phenotype acute leukemia (MPAL), defined by the simultaneous expression of myeloid and lymphoid markers. This hybrid immunophenotype can make diagnosis and treatment challenging [ 1 , 26 ].

Although KMT2A ‐r‐ALL is known for having a worse prognosis than non‐ KMT2A ‐r leukemias, there is significant heterogeneity in outcomes. Several factors influence risk stratification, including age, specific MLL fusion partner, response to treatment, and CNS disease. It is reported that younger patients, particularly babies suffering from KMT2A ‐r‐ALL, frequently have a worse prognosis as compared to adults and older kids. Moreover, the partner gene involved in the KMT2A rearrangement can influence prognosis. Some fusion partners may be associated with a more favorable outcome than others [ 26 , 27 ]. The response to initial treatment is a crucial factor in risk stratification. Patients with a slow or poor response may have a greater chance of relapse. As was previously indicated, the existence of CNS involvement upon diagnosis is a risky factor, and patients with this feature may require more intensive therapy [ 28 ]. Ongoing research is exploring targeted therapies and novel treatment approaches for KMT2A ‐r‐ALL, intending to improve outcomes and reduce relapse rates.

KMT2A ‐Rearranged Acute Myeloid Leukemia ( KMT2A ‐r‐ AML )

KMT2A ‐r‐ALL and KMT2A ‐r‐AML are two distinct subtypes of leukemia, each distinguished by KMT2A rearrangements on a genomic level. Like KMT2A ‐r‐ALL, KMT2A ‐r‐AML is determined by chromosomal translocations involving the KMT2A gene, found on chromosome 11q23. Moreover, Both KMT2A ‐r‐AML and KMT2A ‐r‐ALL are associated with poor prognoses, but the specific prognostic factors and outcomes can vary depending on variables such as genetic subtypes, age, and how they react to treatment. Despite the challenges, treatment strategies and advances continue to improve some patients' survival rates [ 26 ]. Key differences exist in their cell lineage, clinical characteristics, treatment strategies, and prognostic implications. KMT2A ‐r‐AML specifically manifests as an acute myeloid leukemia subtype, often exhibits a complex genetic landscape, and the specific KMT2A fusion partner genes can vary, contributing to the heterogeneity of the disease [ 26 ]. Figure 3 presents the key distinctions between KMT2A ‐r‐ALL and KMT2A ‐r‐AML [ 29 , 30 , 31 ].

Cytogenetics and Immunophenotype

KMT2A ‐r‐AML is a subtype of acute myeloid leukemia that primarily affects cells of the myeloid lineage, which causes the bone marrow to produce an excessive amount of immature myeloid cells [ 11 ]. KMT2A ‐r‐AML often presents with complex karyotypes, indicating multiple chromosomal abnormalities. These complex karyotypes are a hallmark of KMT2A ‐r‐AML and contribute to the disease's aggressiveness [ 11 , 32 ]. In addition to KMT2A rearrangements, KMT2A ‐r‐AML may carry cooperating genetic alterations in genes such as FLT3, NPM1 , and IDH1/2 , further contributing to the disease's pathogenesis and clinical behavior [ 33 , 34 ]. The immunophenotype of KMT2A ‐r‐AML typically shows the manifestations of myeloid markers such as CD33, CD13, and MPO (myeloperoxidase) [ 35 ]. The expression of these markers is consistent with the myeloid lineage differentiation characteristic of AML. KMT2A ‐r‐AML cells may also exhibit hematopoietic stem and progenitor cell markers, such as CD34 and CD117 (c‐kit) [ 35 ]. The presence of these markers suggests that the leukemic cells originate from an immature hematopoietic precursor population. These immunophenotypic and cytogenetic features play crucial roles in diagnosing and classifying AML and can guide treatment decisions [ 33 ].

Clinical Presentation and Risk Stratification

KMT2A ‐r‐AML is characterized by an abrupt onset, rapid advancement, and an extremely bad prognosis in contrast to non‐ KMT2A ‐rearranged cases. The swift multiplication of myeloid cells in AML can lead to symptoms such as tiredness, anemia, and an increased risk of infections [ 1 , 36 ]. Other clinical symptoms include breathing difficulties, bleeding and bruising easily, fever, bone pain, bone marrow failure, headaches, night sweats, and weight loss. The prognosis of KMT2A ‐r‐AML is dependent on variables like the patient's age, specific KMT2A fusion partner, other chromosomal abnormalities, and overall health [ 31 ]. The European LeukemiaNet (ELN) risk stratification system classifies KMT2A ‐r‐AML into three risk categories: favorable, intermediate, and poor. In the favorable risk group, there is the translocation of t(9;11)(p22;q23) in patients and no other chromosomal abnormalities. These patients are typically young and have a decreased number of white blood cells at diagnosis. Patients with other KMT2A rearrangements or chromosomal abnormalities, in addition to KMT2A rearrangements, have an intermediate prognosis. These patients are typically older and have a higher white blood cell count at diagnosis [ 29 ]. KMT2A‐AFF1 ( MLL‐AF4 ) gene fusion presents symptoms such as hepatosplenomegaly, coagulopathy, and severe organ infiltration. Affected individuals who do not experience remission with standard chemotherapy are considered high risk and may require more aggressive treatment approaches, such as the transplantation of hematopoietic stem cells. These individuals may be candidates for stem cell transplantation, innovative therapies, or experimental treatments.

Current and Exploratory Therapeutic Targets

KMT2A ‐r acute leukemia therapeutic targets have been the subject of intensive research due to the aggressive nature of these leukemias. These therapies can be grouped based on the key component of the KMT2A ‐r acute leukemia microenvironment being targeted.

Targeting KMT2A Fusion Proteins

Central to KMT2A ‐r leukemia are KMT2A fusion proteins, which are the product of chromosomal translocations. Research has focused on targeting these fusion proteins directly. Small molecule inhibitors and monoclonal antibodies are being explored to disrupt the function of KMT2A fusion proteins. For example, studies have explored the target of Menin‐KMT2A [ 2 , 32 ] and KMT2A‐AFF1 (MLL‐AF4) [ 13 , 37 ] interactions. The Menin protein is crucial for KMT2A to regulate the expression of pertinent target genes, as well as facilitate the high‐affinity interactions occurring between the amino termini of KMT2A proteins. Menin proteins are also required to facilitate KMT2A fusion protein oncogenic transformation [ 38 ]. Thus, for KMT2A ‐r leukemias, one possible treatment approach is to hinder the Menin‐KMT2A interaction. According to recent literature, the FDA has designated Menin‐KMT2A interaction inhibitors like SNDX‐5613 and KO‐539 as orphan drugs for the treatment of refractory/relapsed leukemia and AML, respectively [ 32 , 39 ]. Relapse is associated with a lineage flip from ALL to AML, which can cause chemotherapy and immunotherapy resistance, leading to poor clinical outcomes [ 7 ]. According to a study, MLL‐AF4 cells exhibit increased expression of immunoproteasomes unique to lymphoid tissues and are responsive to pharmacologically relevant doses of the immunoproteasome inhibitor ONX‐0914. In MLL‐AF4 ALL, the inhibitors ONX‐0914 and LU‐102 exhibit synergistic cytotoxicity, and ONX‐0914 markedly delays the development of mice with orthotopic ALL xenograft tumors [ 40 ]. Inhibitors to other regular fusions of KMT2A (MLL), such as MLL‐ENL, MLL‐AF10, MLL‐AF4, and MLL‐AF9, as well as their mode of action, have been explored [ 41 ].

Epigenetic Regulators

KMT2A fusion proteins often influence epigenetic regulation, leading to aberrant gene expression. Therapies targeting epigenetic modifiers, including DNA methyltransferase inhibitors and histone deacetylase (HDAC) inhibitors, aim to correct the epigenetic dysregulation seen in KMT2A ‐r leukemia. Vorinostat and panobinostat are HDAC inhibitors that affect histone acetylation, whereas 5‐azacitidine and decitabine are used to target DNA methylation [ 42 ]. In a recent study, the authors explored the impact of the potent HDAC inhibitor, I1, and its potential mechanism on cells of KMT2A ‐r‐AML and KMT2A ‐r‐ALL. They found that I1 provokes KMT2A ‐r‐AML and KMT2A ‐r‐ALL cells to differentiate via epigenetic modification as it significantly inhibited the proliferation and the colony‐forming ability of the cancer cells by promoting cell differentiation, combined with the blockage of the cell cycle at the G0/G1 phase [ 43 ]. This offers an epigenetic regulator, such as I1, as an effective epigenetic drug to prevent differentiation block in KMT2A ‐r acute leukemia patients, and it would be promising for treating acute leukemias. Another study observed reduced Eμ‐Myc lymphoma proliferation and differentiation in acute promyelocytic leukemia using the HDAC3 inhibitor RGFP96 (APL). In both in vitro and in vivo settings, genetic co‐depletion of Hdac1 and Hdac2 was pro‐apoptotic in Eμ‐Myc lymphoma, and this behavior was mimicked by the HDAC1/2‐specific agent RGFP233 [ 44 ]. It has been demonstrated that other HDAC inhibitors, such as I3 [ 45 ] and I13 [ 46 ], are strong chromatin‐remodeling agents that can overcome the differentiation block in AML patients, including those with t(8; 21) translocation or KMT2A rearrangements. These inhibitors may be a potent and specific therapy option for AML. In addition to vorinostat and panobinostat, other HDAC inhibitors approved by the FDA for hematological malignancies are romidepsin and belinostat, and they inhibit class II and/or class I HDACs, including HDAC1, 2, 3, and 6 [ 44 ].

By integrating into DNA, hypomethylating substances like decitabine and azacitidine lessen DNA hypermethylation. In cases of acute lymphoblastic leukemia with KMT2A rearrangements, decitabine significantly delays leukemic proliferation in vivo xenograft models and inhibits proliferation in vitro by provoking the arrest of cell cycle arrest in the G0/G1 phase and apoptosis [ 47 ]. These studies provide evidence of the potential of these epigenetic regulators in KMT2A ‐r acute leukemias and warrant more clinical evaluation.

Transcriptional Dependencies

Transcriptional dependencies that arise from KMT2A fusions provide therapeutic opportunities. Inhibitors of specific transcriptional co‐activators or elongation factors that interact with KMT2A fusion proteins can disrupt leukemic transcriptional programs. Therapeutic elements such as bromodomain‐containing protein 4 (BRD4), disruptor of telomeric silencing 1‐like (DOT1L), and SET inhibitors have gained much research interest and have advanced into clinical trials. For example, the DOT1L inhibitor EPZ‐5676 has shown moderate clinical activity in KMT2A ‐r acute leukemia clinical trials [ 41 , 48 ]. It is also reported that small‐molecule inhibition or genetic disruption of DOT1L and BRD4 shows significant synergistic activity against KMT2A ‐r leukemia cell lines [ 49 ]. Moreover, when made to work together, SIRT1 activators and DOT1L inhibitors exhibit increased antiproliferative action against KMT2A ‐r leukemia cells [ 50 ]. In other studies, super elongation complex (SEC) inhibitors such as THZ1 and THZ531 serve as small molecules that target SEC, disrupting transcription elongation [ 51 , 52 ]. Through apoptosis induction and cell proliferation inhibition, THZ1 exhibits anti‐tumor actions in a variety of cancers. In a study, AML cell viability was found to be decreased by THZ1, which also activated G0/G1 cell cycle arrest, induced apoptosis in a time‐ and dose‐dependent manner, downregulated the phosphorylation of CDK1 and CDK2, and decreased RNA Pol II phosphorylation at several serine sites [ 53 ]. The activation of CDKs, or cyclin‐dependent kinases, is involved in the unrestrained growth of tumor cells. Thus, CDK inhibitors such as CYC065 and THZ1 disrupt leukemic transcriptional programs by reducing CDKs, leading to suppressed invasion, induced viability loss due to the arrest of the G2/M cell cycle, decreased proliferation, and promoted apoptosis [ 54 ]. Together, these findings highlight the potential of these therapeutic agents to suppress tumor growth and promote the death of cells, warranting further clinical investigation.

FLT3 and Other Signaling Pathways

Aberrant activation of FLT3 and other signaling pathways is common in KMT2A ‐r‐AML. Small molecule inhibitors targeting FLT3 and other kinases like JAK2 (Janus‐kinase 2) and PI3K (phosphoinositid‐3‐kinasen) have shown promise in preclinical studies. FLT3 inhibitors such as midostaurin and gilteritinib [ 55 ] target FLT3 mutations seen in AML, while JAK2 inhibitors such as ruxolitinib [ 56 ] inhibit JAK2, which may be activated in KMT2A ‐r leukemia. Moreover, PI3K inhibitors such as idelalisib and copanlisib have been documented [ 57 ]. The combined use of selective small‐molecule kinase inhibitors of FLT3 phosphorylation and Menin‐KMT2A inhibition results in a marked downregulation of phosphorylated FLT3 and downstream transcriptional genes of FLT3 signaling. Synergistic suppression of proliferation was triggered by this particular drug combination and increased apoptosis in KMT2A ‐r leukemias with an FLT3 mutation as opposed to single‐drug therapy. It also reduced leukemia burden and prolonged survival in KMT2A ‐r FLT3mut leukemia mice [ 58 ]. In a similar study, apoptosis is potently and synergistically triggered in FLT3‐ITD AML cell lines and primary patient samples when the FLT3 inhibitors gilteritinib or midostaurin are combined with the Bcl‐2 inhibitor venetoclax. The FLT3 inhibitors downregulate Mcl‐1, increasing the activity of venetoclax. Moreover, in vivo results show that the administration of gilteritinib and venetoclax together has therapeutic potential [ 55 ].

In individuals of various age groups, including newborns, kids, and grownups diagnosed with KMT2A ‐r‐ALL, as well as children with KMT2A ‐r‐AML, there are notable increases in the levels of gene expression of SYK , FLT3 , JAK2/JAK3 , BTK , and several SRC family protein tyrosine kinases ( PTK ). Additionally, in the case of grownups with KMT2A ‐r‐AML, distinct alterations in gene expression were observed, particularly increases in JAK family kinase TYK2, SYK, and the SRC family kinases FGR and HCK [ 59 ]. This offers tyrosine kinases, among other signaling pathways in KMT2A ‐r acute leukemias as possible treatment targets for beating drug resistance in cancer.

Proteasome Inhibition

Proteolysis‐targeting chimera (PROTAC) degraders have been investigated as a possible therapeutic alternative to inhibit canonical and non‐canonical oncogenic activity [ 60 ]. In a recent study, a new and extremely powerful EZH2 PROTAC degrader, MS8847, was found to trigger antiproliferative effects and degradation of EZH2 in KMT2A ‐r‐AML cells [ 61 ]. Targeting the proteasome with drugs like bortezomib can disrupt the degradation of specific proteins, including tumor suppressors, leading to apoptosis in KMT2A ‐r leukemia cells. The proteasome inhibitors carfilzomib and bortezomib have shown clinical efficacy in treating ALL and are authorized for the treatment of multiple myeloma and mantle cell lymphoma [ 40 ]. It is observed that bortezomib effectively restrained cell growth and reduced the formation of colonies in the leukemia cells of humans and also murine leukemia cells. Additionally, LSC (Leukemia Stem Cell) frequency and function were reduced by bortezomib, hindered disease advancement, and prolonged the general survival in mice with MLL‐AF9‐rearranged leukemia. Furthermore, bortezomib resulted in a reduction in the proportion of human LSC (characterized by CD34+ CD38‐ phenotype) and increased the general survival in mice engrafted with AML blasts, particularly in the NOD/SCID‐IL2Rγ (NSG) model [ 62 ]. Similarly, bortezomib demonstrated a dosage‐dependent increase in the development of miR‐29b in AML cells in vitro, leading to reduced levels of DNA methyltransferases (Dnmts), inhibited cell proliferation, and an enhanced rate of programmed cell death (apoptosis). However, in vivo administration of bortezomib against dKI AML showed no efficacy. In contrast, when administered as a single agent in vivo, liposome‐encapsulated bortezomib successfully reversed the reduction of miR‐29b expression and provoked a long‐term remission free of illness lasting 90 days in 80% of dKI AML mice. Notably, these mice initially had a great burden of leukemia at the beginning of the treatment and exhibited no signs of relapse upon autopsy [ 63 ]. Therefore, when used alone, liposomal bortezomib effectively eliminates Mll(PTD/wt):Flt3(ITD/wt) AML in mouse models. This approach holds significant promise as a potent and possibly therapeutic approach for human diseases that are at risk.

On the contrary, although the proteasome inhibitor, carfilzomib, demonstrated in vitro synergy with a number of traditional chemotherapeutic agents such as vincristine, dexamethasone, daunorubicin, L‐asparaginase, and 4‐hydroperoxycyclophosphamide, it failed to produce survival advantage for either carfilzomib monotherapy or combined therapy with multiple chemotherapeutic agents in both high or low disease burden [ 64 ]. This underscores that although proteasome inhibitors are crucial in treating various blood‐related cancers, their effectiveness in the in vitro setting may not always align with their real in vivo benefits. It emphasizes the significance of validating their performance in living organisms before considering them for clinical application. Thus, more clinical explorations are needed.

Immunotherapies

Immunotherapeutic strategies, such as chimeric antigen receptor (CAR) T‐cell therapy and antibody‐drug conjugates, are being explored to target specific cell surface markers present in KMT2A ‐r leukemia cells. CD19‐targeted CAR‐T cells (e.g., tisagenlecleucel) have been used in B‐cell ALL [ 65 ]. Moreover, drug‐antibody conjugates such as inotuzumab ozogamicin target CD22 and are documented in treating relapsed or refractory ALL [ 66 , 67 ]. In a clinical study, authors assessed the treatment outcome of kids and youthful adults with relapsed/refractory CD19+ ALL/lymphoblastic lymphoma treated on 5 CD19‐directed CAR T‐cell (CTL019 or humanized CART19) clinical trials or with commercial tisagenlecleucel. According to the results, the complete remission rate was 94%, with no disparity between strata according to their risk categories. Additionally, there was no distinction between overall survival (OS) and relapse‐free survival [ 65 ]. Thus, CTL019, huCART19, and tisagenlecleucel successfully achieved long‐lasting remissions in various cytogenetic categories [ 65 ]. Patients who have relapsed or are refractory and have cytogenetics that are high‐risk, such as those with KMT2A ‐r iALL, showed a notable increase in the likelihood of overall survival (OS) and relapse‐free survival (RFS) at the two‐year mark [ 65 ].

Tisagenlecleucel and huCART19 effectively treat diseases of the central nervous system (CNS) and maintain long‐lasting periods of remission in young patients with lymphocytic lymphoma or B‐cell ALL that has relapsed or is refractory. Importantly, they do so without significantly raising the risk of severe neurotoxicity [ 68 ]. However, it is advisable to exercise caution regarding the timing of disease management and therapy to minimize this potential harm. These initial results encourage the utilization of these CAR T‐cell therapies for patients dealing with CNS‐relapsed or refractory B‐cell ALL. Several investigations have shown the encouraging potential of immunoproteasome inhibitors KZ‐616 and M3258 in ALL [ 40 ].

Synthetic Lethality

Identifying synthetically lethal genes with KMT2A fusion genes has opened new avenues for therapeutic development. Synthetic lethality‐based therapies target the vulnerabilities specific to KMT2A ‐r leukemias. For example, drugs that inhibit poly‐ADP ribose polymerase (PARP), such as olaparib target synthetic lethality with mutations in genes responsible for DNA repair. As a cancer treatment, PARP inhibitors prevent the PARP from carrying out its repair activity in cancer cells, causing the cells to die [ 69 , 70 ]. Combining olaparib with DNMT inhibitors or chemotherapy leads to a significant decrease in the creation of colonies of cells or cell growth and induces the blocking of the cell cycle and programmed cell death in MLL‐AF9 leukemic cells when compared to using these agents individually [ 71 ]. Another study found that AML fueled by repressive transcription factors, such as PML‐RARα fusion oncoproteins (resulting from PML‐RARA ) and AML1‐ETO (resulting from the fusion oncogene RUNX1‐RUNX1T1 ) display high sensitivity to inhibition of PARP. This heightened sensitivity is attributed to their decreased production of critical homologous recombination (HR)‐related genes and their impaired response to damaged DNA (DDR). In contrast, leukemia caused by KMT2A fusions with strong transactivation capabilities demonstrates DDR proficiency and resistance to PARP inhibition [ 72 ]. Moreover, while the blockage of HOXA9, an KMT2A downstream target, sensitizes KMT2A ‐r leukemia to PARP inhibitors and impairs DDR, the overexpression of HOXA9 rather confers PARP inhibitor resistance to AML1‐ETO and PML‐RARα transformed cells [ 72 ]. Furthermore, PARP inhibitors olaparib and Temozolomide specifically cause leukemic cells that are positive for TCF3‐HLF to become toxic [ 73 ]. These observations present an innovative therapeutic strategy for combating refractory leukemia, including those with KMT2A ‐r in both AML and ALL.

Stem Cell Transplantation

In high‐risk cases, transplanting allogeneic stem cells is thought to be a curative approach. This approach involves replacing the diseased individual's hematopoietic system with healthy cells from a donor. Stem cell transplants may involve genetically matched donors and recipients to minimize the chances of graft‐versus‐host disease. In a clinical study of patients with MLL / KMT2A rearrangement, it was found that solid tumor therapy‐related AML (t‐AML), MLL t‐AML, had bad prognosis in comparison to non‐MLL t‐AML and MLL de novo AML, but allogeneic hematopoietic stem cell transplantation (allo‐HSCT) overcame the poor prognosis of MLL t‐AML [ 74 ]. According to a related study, individuals treated with allo‐HSCT have a better prognosis and higher survival rates than those treated with chemotherapy alone when it comes to treating KMT2A ‐r‐AML [ 75 ]. However, KMT2A ‐r‐AML patients who experienced thrombocytopenia at the beginning (< 50 × 10 9 ) had extremely poor OS and disease‐free survival (DFS) [ 75 ]. There is also a case report of a person with 11q23/ KMT2A ‐r‐AML who had a third allo‐HSCT successfully after undergoing treatment with azacitidine and venetoclax. The result indicates that a combined therapy of allo‐HSCT with azacitidine and venetoclax might be a successful strategy for relapsed and refractory KMT2A ‐r‐AML [ 76 ]. Other combined therapies, such as venetoclax‐containing myeloablative conditioning (MAC) allo‐HSCT regimens, are reported to be safe, practical, and efficient for patients with high‐risk AML [ 77 ]. Despite these promising outcomes, clinical data on this subject are largely lacking, and the few existing studies are primarily small‐scale. More large‐scale clinical studies are needed.

Clinical Trials

Extensive clinical trials are currently evaluating numerous therapeutic targets in KMT2A ‐r leukemia from the Clinical Study Database ( ClinicalTrials.gov ), thereby affording patients access to innovative and groundbreaking therapeutic interventions. Participation in clinical trials can provide opportunities to benefit from the latest therapeutic strategies. In KMT2A ‐r leukemias, menin is a protein essential for transforming blood cells into cancer cells. Menin inhibition leads to the death of leukemia cells by triggering differentiation and apoptosis [ 32 , 78 ]. NPM1 is another protein that is important in the development of leukemia. It binds to DNA at specific sites that KMT2A also occupies. Inhibiting menin triggers the degradation of NPM1, which leads to a reduction in the expression of genes essential for leukemia cells to grow and survive [ 79 ]. Therefore, disrupting the menin‐KMT2A axis is a promising treatment approach for tackling leukemias driven by KMT2A rearrangements and NPM1 mutations. There are at least six distinct menin‐KMT2A inhibitors that are currently being evaluated in clinical trials as first‐ and second‐line monotherapy for acute leukemias (DSP‐5336, BMF‐219, DS‐1594, JNJ‐75276617, ziftomenib, and revumenib) [ 80 ]. for two of these inhibitors, revumenib and ziftomenib, which have shown promising results [ 80 ]. In an efficacy analysis of the phase 1 clinical trial of revumenib (SNDX‐5613), In KMT2A ‐r or NPM1 ‐mutant acute leukemia, the authors report a 30% rate of full remission or complete remission with partial hematologic recovery and a low frequency of Grade 3 or higher treatment‐related side events [ 2 ]. This clinical data established menin inhibition as a treatment approach for susceptible subtypes of acute leukemia.

In a risk‐stratified therapeutic study of babies suffering from KMT2A ‐r ALL, patients were given high‐dose cytarabine along with modified chemotherapy, and only high‐risk patients were eligible for HSCT. Newborns with KMT2A ‐r ALL (Intermediate + high risk) had a 3‐year event‐free survival (EFS) rate of 66.2%, while newborns with germline KMT2A ( KMT2A ‐g) ALL (low risk) had a rate of 93.3%. For patients at moderate risk, the 3‐year EFS rate was 94.4%, while for those at high risk, it was 56.6% [ 81 ]. This indicates the importance of risk stratification and the implementation of rigorous chemotherapy in leukemia interventions, which should be considered in future trials. In an international phase III randomized study that investigated whether myeloid‐style consolidation chemotherapy is better than lymphoid style, patients receive either the lymphoid course (low‐dose cytosine arabinoside [araC], cyclophosphamide (IB)), 6‐mercaptopurine or experimental myeloid courses (araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE)). It was concluded that early intensification of treatment with post‐induction myeloid‐type chemotherapy did not result in better outcomes for infants with ALL in contrast to the standard lymphoid‐type chemotherapy. The results of the Interfant‐06 trial for newborns with ALL were not better than those in the Interfant‐99 trial, which was conducted earlier [ 82 ]. In other words, adding more and more potent chemotherapy drugs to the early treatment of infant ALL did not make a difference in how well the children did. This is important information for doctors and parents to know when making decisions about how to treat infants ALL. Moreover, this provides an avenue for further exploration to consolidate apparent contradictions and improve existing and evolving therapies. The therapeutic targets expanded above are listed in Table 1 as a summary.

Conclusion and Perspective

KMT2A ‐r acute leukemia is linked to a poor treatment outcome. This subtype of leukemia is often resistant to conventional chemotherapy, leading to decreased rates of remission and greater rates of relapse compared to other leukemia types. The aggressive nature of KMT2A ‐r acute leukemia contributes to its challenging treatment landscape. Typically, treatment strategies for KMT2A ‐r acute leukemia involve vigorous chemotherapy regimens, transplantation of stem cells, and specific therapies. While some patients may achieve remission, long‐term survival rates remain relatively low, especially in cases of adult KMT2A ‐r acute leukemia. Research is ongoing to develop more effective and targeted treatments for KMT2A ‐r acute leukemia, but it remains a challenging disease to manage. Prognosis and treatment outcomes may vary depending on factors like age, specific KMT2A rearrangement, and the presence of other genetic mutations.

Regardless, the perspective and prospects of KMT2A ‐r acute leukemia research are promising and include several key aspects. Firstly, researchers are actively investigating targeted therapies specific to KMT2A ‐r acute leukemia. These therapies aim to disrupt the KMT2A fusion proteins, which are essential to the illness. Identifying and developing drugs that target these fusion proteins could significantly improve treatment outcomes. Secondly, immunotherapeutic approaches, such as CAR T‐cell therapy, hold potential in treating KMT2A ‐r leukemia. CAR T‐cell therapies are being explored to specifically target and eliminate leukemia cells, potentially leading to more effective treatments. Moreover, advances in genomic sequencing continue to provide a deeper understanding of the genetic alterations associated with KMT2A ‐r leukemia. This knowledge can guide the development of precision medicine strategies and the identification of new therapeutic targets. In addition, researchers are exploring combinations of existing treatments, such as chemotherapy, epigenetic modifiers, and targeted therapies, to enhance the prognosis for patients with KMT2A ‐r leukemia. Combinatorial approaches aim to maximize treatment efficacy while minimizing side effects. For example, a study reports that the strongest antiproliferative effects in KMT2A ‐r‐ALL are observed when the cancer cells are simultaneously exposed to hypomethylating agents (azacitidine and decitabine) and cytostatic drugs (cytarabine and doxorubicin). Cytarabine was used to provoke the most powerful synergistic effects of hypomethylating drugs [ 47 ]. This opens the front for further clinical exploration of combined therapies.

Identifying reliable biomarkers for KMT2A ‐r leukemia can aid in early detection, risk stratification, and treatment monitoring. Biomarker research is essential for developing personalized treatment plans; thus, there is a need for more future studies in this direction. Due to the essential role of clinical trials in testing and validating new treatment approaches, more trials are needed in future studies. This contributes to advancing the field and subsequent translation in the clinical setting. Improving the overall care and support for KMT2A ‐r leukemia patients is a crucial aspect of research. This includes enhancing supportive care, managing side effects, and addressing the unique needs of this patient population. Finally, future studies should consider collaborative efforts between researchers and institutions worldwide to accelerate progress in KMT2A ‐r leukemia research. Sharing knowledge, data, and resources is vital for significantly advancing this critical disease.

In summary, the future of KMT2A ‐r acute leukemia research is marked by a deepening understanding of the disease's biology, a focus on personalized treatments, immunotherapies, genomics, and innovative combinations of therapies. The ultimate goal is to improve patient outcomes, reduce the burden of illness, and improve the affected people's quality of life. Research and clinical exploration in this field are still ongoing and hold the prospect of improving therapeutic approaches and patient outcomes.

Author Contributions

Lei Yin: writing – original draft (lead). Lin Wan: writing – review and editing (equal). Youjian Zhang: investigation (equal), resources (equal), validation (equal), visualization (equal). Shenghao Hua: formal analysis (equal), validation (equal), visualization (equal). Xuejun Shao: writing – review and editing (equal).

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

The authors have nothing to report.

Data Availability Statement

The authors have nothing to report.

References

1 S. Cantilena , L. Gasparoli , D. Pal , et al., “ Direct Targeted Therapy for MLL‐Fusion‐Driven High‐Risk Acute Leukaemias ,” Clinical and Translational Medicine 12 , no. 6 ( 2022 ): e933 . 35730653 10.1002/ctm2.933 PMC9214753

2 G. C. Issa , I. Aldoss , J. DiPersio , et al., “ The Menin Inhibitor Revumenib in KMT2A‐Rearranged or NPM1‐Mutant Leukaemia ,” Nature 615 , no. 7954 ( 2023 ): 920 – 924 . 36922593 10.1038/s41586-023-05812-3 PMC10060155

3 B. J. Aubrey , J. A. Cutler , W. Bourgeois , et al., “ IKAROS and MENIN Coordinate Therapeutically Actionable Leukemogenic Gene Expression in MLL‐r Acute Myeloid Leukemia ,” Nature Cancer 3 , no. 5 ( 2022 ): 595 – 613 . 35534777 10.1038/s43018-022-00366-1 PMC9404532

4 W. Zhu , Y. Ding , W. Huang , et al., “ Synergistic Effects of the KDM4C Inhibitor SD70 and the Menin Inhibitor MI‐503 Against MLL::AF9‐Driven Acute Myeloid Leukaemia ,” British Journal of Haematology 205 , no. 2 ( 2024 ): 568 – 579 . 38877874 10.1111/bjh.19591

5 A. J. Belt , S. Grant , R. M. Tombes , and S. C. Rothschild , “ Myeloid Targeted Human MLL‐ENL and MLL‐AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos ,” PLoS Genetics 20 , no. 6 ( 2024 ): e1011308 . 38829886 10.1371/journal.pgen.1011308 PMC11175583

6 C. Meyer , P. Larghero , B. Almeida Lopes , et al., “ The KMT2A Recombinome of Acute Leukemias in 2023 ,” Leukemia 37 , no. 5 ( 2023 ): 988 – 1005 . 37019990 10.1038/s41375-023-01877-1 PMC10169636

7 R. Tirtakusuma , K. Szoltysek , P. Milne , et al., “ Epigenetic Regulator Genes Direct Lineage Switching in MLL/AF4 Leukemia ,” Blood 140 , no. 17 ( 2022 ): 1875 – 1890 . 35839448 10.1182/blood.2021015036 PMC10488321

8 T. L. Lin , A. K. Jaiswal , A. J. Ritter , et al., “ Targeting IGF2BP3 Enhances Antileukemic Effects of Menin‐MLL Inhibition in MLL‐AF4 Leukemia ,” Blood Advances 8 , no. 2 ( 2024 ): 261 – 275 . 38048400 10.1182/bloodadvances.2023011132 PMC10824693

9 M. Li , Y. Z. Zheng , J. Li , et al., “ Clinical Characteristics and Prognosis of MLL Rearranged Childhood Acute Lymphocyte Leukemia ,” Zhongguo Shi Yan Xue Ye Xue Za Zhi 31 , no. 4 ( 2023 ): 973 – 979 . 37551464 10.19746/j.cnki.issn.1009-2137.2023.04.007

10 C. Tretti Parenzan , A. D. Molin , G. Longo , et al., “ Functional Relevance of circRNA Aberrant Expression in Pediatric Acute Leukemia With KMT2A::AFF1 Fusion ,” Blood Advances 8 , no. 5 ( 2024 ): 1305 – 1319 . 38029383 10.1182/bloodadvances.2023011291 PMC10918493

11 B. A. Lopes , C. P. Poubel , C. E. Teixeira , et al., “ Novel Diagnostic and Therapeutic Options for KMT2A‐Rearranged Acute Leukemias ,” Frontiers in Pharmacology 13 ( 2022 ): 749472 . 35734412 10.3389/fphar.2022.749472 PMC9208280

12 S. Iyoda , K. Yoshida , K. Shoji , et al., “ KRAS G12 Mutations as Adverse Prognostic Factors in KMT2A‐Rearranged Acute Myeloid Leukemia ,” Leukemia 38 , no. 7 ( 2024 ): 1609 – 1612 . 38632314 10.1038/s41375-024-02244-4

13 N. T. Crump , A. L. Smith , L. Godfrey , et al., “ MLL‐AF4 Cooperates With PAF1 and FACT to Drive High‐Density Enhancer Interactions in Leukemia ,” Nature Communications 14 , no. 1 ( 2023 ): 5208 . 10.1038/s41467-023-40981-9 PMC10457349 37626123

14 M. Górecki , I. Kozioł , A. Kopystecka , J. Budzyńska , J. Zawitkowska , and M. Lejman , “ Updates in KMT2A Gene Rearrangement in Pediatric Acute Lymphoblastic Leukemia ,” Biomedicine 11 , no. 3 ( 2023 ): 821 . 10.3390/biomedicines11030821 PMC10045821 36979800

15 E. B. Heikamp , J. A. Henrich , F. Perner , et al., “ The Menin‐MLL1 Interaction Is a Molecular Dependency in NUP98‐Rearranged AML ,” Blood 139 , no. 6 ( 2022 ): 894 – 906 . 34582559 10.1182/blood.2021012806 PMC8832476

16 T. A. Milne , “ Chromatin and Aberrant Enhancer Activity in KMT2A Rearranged Acute Lymphoblastic Leukemia ,” Current Opinion in Genetics & Development 86 ( 2024 ): 102191 . 38579381 10.1016/j.gde.2024.102191 PMC7619017

17 W. Wu , Y. Jiang , D. Xing , et al., “ The Epigenetic Regulators EP300/CREBBP Represent Promising Therapeutic Targets in MLL‐Rearranged Acute Myeloid Leukemia ,” Cell Death Discovery 10 , no. 1 ( 2024 ): 206 . 38693103 10.1038/s41420-024-01940-5 PMC11063202

18 F. Pan , M. Iwasaki , W. Wu , et al., “ Enhancer Remodeling Drives MLL Oncogene‐Dependent Transcriptional Dysregulation in Leukemia Stem Cells ,” Blood Advances 7 , no. 11 ( 2023 ): 2504 – 2519 . 36705973 10.1182/bloodadvances.2022008787 PMC10248086

19 X. Zhou and R. Lu , “ HOXA9/MEIS1 Targets in Leukemia: Reinforced Signaling Networks and Therapeutic Opportunities ,” Haematologica 108 , no. 5 ( 2023 ): 1205 – 1207 . 36005566 10.3324/haematol.2022.281779 PMC10153530

20 N. Meriç , E. Albayrak , Z. Gülbaş , and F. Kocabaş , “ MEIS Inhibitors Reduce the Viability of Primary Leukemia Cells and Stem Cells by Inducing Apoptosis ,” Leukemia & Lymphoma 65 , no. 2 ( 2024 ): 187 – 198 . 37902585 10.1080/10428194.2023.2275532

21 M. W. M. Kühn and A. Ganser , “ The Menin Story in Acute Myeloid Leukaemia‐The Road to Success ,” British Journal of Haematology ( 2024 ), Epub ahead of print. 10.1111/bjh.19508 38710595

22 X. N. Zhu , Y. S. Wei , Q. Yang , et al., “ FBXO22 Promotes Leukemogenesis by Targeting BACH1 in MLL‐Rearranged Acute Myeloid Leukemia ,” Journal of Hematology & Oncology 16 , no. 1 ( 2023 ): 9 . 36774506 10.1186/s13045-023-01400-0 PMC9922468

23 Y. Sheng , C. Yu , Y. Liu , et al., “ FOXM1 Regulates Leukemia Stem Cell Quiescence and Survival in MLL‐Rearranged AML ,” Nature Communications 11 , no. 1 ( 2020 ): 928 . 10.1038/s41467-020-14590-9 PMC7026046 32066721

24 T. Candelli , P. Schneider , P. Garrido Castro , et al., “ Identification and Characterization of Relapse‐Initiating Cells in MLL‐Rearranged Infant ALL by Single‐Cell Transcriptomics ,” Leukemia 36 , no. 1 ( 2022 ): 58 – 67 . 34304246 10.1038/s41375-021-01341-y PMC8727302

25 S. H. R. Lee , E. Ashcraft , W. Yang , et al., “ Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL ,” Journal of Clinical Oncology 41 , no. 35 ( 2023 ): 5422 – 5432 . 37729596 10.1200/JCO.23.00880 PMC10852380

26 L. Pagliaro , S. J. Chen , D. Herranz , et al., “ Acute Lymphoblastic Leukaemia ,” Nature Reviews. Disease Primers 10 , no. 1 ( 2024 ): 41 . 10.1038/s41572-024-00525-x 38871740

27 A. Bataller , T. Abuasab , D. McCall , et al., “ Myeloid Lineage Switch in KMT2A‐Rearranged Acute Lymphoblastic Leukemia Treated With Lymphoid Lineagedirected Therapies ,” Haematologica 109 , no. 1 ( 2024 ): 293 – 297 . 37646654 10.3324/haematol.2023.283705 PMC10772528

28 M. Thastrup , A. Duguid , C. Mirian , K. Schmiegelow , and C. Halsey , “ Central Nervous System Involvement in Childhood Acute Lymphoblastic Leukemia: Challenges and Solutions ,” Leukemia 36 , no. 12 ( 2022 ): 2751 – 2768 . 36266325 10.1038/s41375-022-01714-x PMC9712093

29 D. Grimwade , R. K. Hills , A. V. Moorman , et al., “ Refinement of Cytogenetic Classification in Acute Myeloid Leukemia: Determination of Prognostic Significance of Rare Recurring Chromosomal Abnormalities Among 5876 Younger Adult Patients Treated in the United Kingdom Medical Research Council Trials ,” Blood 116 , no. 3 ( 2010 ): 354 – 365 . 20385793 10.1182/blood-2009-11-254441

30 H. Döhner , A. H. Wei , F. R. Appelbaum , et al., “ Diagnosis and Management of AML in Adults: 2022 Recommendations From an International Expert Panel on Behalf of the ELN ,” Blood 140 , no. 12 ( 2022 ): 1345 – 1377 . 35797463 10.1182/blood.2022016867

31 X. Chen , H. Zhu , C. Qiao , et al., “ Next‐Generation Sequencing Reveals Gene Mutations Landscape and Clonal Evolution in Patients With Acute Myeloid Leukemia ,” Hematology 26 , no. 1 ( 2021 ): 111 – 122 . 33491606 10.1080/16078454.2020.1858610

32 H. Bai , S. Q. Zhang , H. Lei , F. Wang , M. Ma , and M. Xin , “ Menin‐MLL Protein‐Protein Interaction Inhibitors: A Patent Review (2014‐2021) ,” Expert Opinion on Therapeutic Patents 32 , no. 5 ( 2022 ): 507 – 522 . 35202550 10.1080/13543776.2022.2045947

33 A. Hernández‐Sánchez , T. González , M. Sobas , et al., “ Rearrangements Involving 11q23.3/KMT2A in Adult AML: Mutational Landscape and Prognostic Implications ‐ a HARMONY Study ,” Leukemia 38 , no. 9 ( 2024 ): 1929 – 1937 . 38965370 10.1038/s41375-024-02333-4 PMC11347382

34 K. Y. Yuen , Y. Liu , Y. Z. Zhou , et al., “ Mutational Landscape and Clinical Outcome of Pediatric Acute Myeloid Leukemia With 11q23/KMT2A Rearrangements ,” Cancer Medicine 12 , no. 2 ( 2023 ): 1418 – 1430 . 35833755 10.1002/cam4.5026 PMC9883550

35 L. Muñoz , J. F. Nomdedéu , N. Villamor , et al., “ Acute Myeloid Leukemia With MLL Rearrangements: Clinicobiological Features, Prognostic Impact and Value of Flow Cytometry in the Detection of Residual Leukemic Cells ,” Leukemia 17 , no. 1 ( 2003 ): 76 – 82 . 12529663 10.1038/sj.leu.2402708

36 E. Zerkalenkova , S. Lebedeva , A. Kazakova , et al., “ Acute Myeloid Leukemia With t(10;11)(p11‐12;q23.3): Results of Russian Pediatric AML Registration Study ,” International Journal of Laboratory Hematology 41 , no. 2 ( 2019 ): 287 – 292 . 30624859 10.1111/ijlh.12969

37 P. Schneider , N. T. Crump , S. Arentsen‐Peters , et al., “ Modelling Acquired Resistance to DOT1L Inhibition Exhibits the Adaptive Potential of KMT2A‐Rearranged Acute Lymphoblastic Leukemia ,” Experimental Hematology & Oncology 12 , no. 1 ( 2023 ): 81 . 37740239 10.1186/s40164-023-00445-8 PMC10517487

38 Q. Shi , M. Xu , Z. Kang , M. Zhang , and Y. Luo , “ Menin‐MLL1 Interaction Small Molecule Inhibitors: A Potential Therapeutic Strategy for Leukemia and Cancers ,” Molecules 28 , no. 7 ( 2023 ): 3026 . 37049787 10.3390/molecules28073026 PMC10095982

39 K. W. DiNardo , T. W. LeBlanc , and H. Chen , “ Novel Agents and Regimens in Acute Myeloid Leukemia: Latest Updates From 2022 ASH Annual Meeting ,” Journal of Hematology & Oncology 16 , no. 1 ( 2023 ): 17 . 36869366 10.1186/s13045-023-01411-x PMC9983204

40 T. W. Jenkins , S. L. Downey‐Kopyscinski , J. L. Fields , et al., “ Activity of Immunoproteasome Inhibitor ONX‐0914 in Acute Lymphoblastic Leukemia Expressing MLL‐AF4 Fusion Protein ,” Scientific Reports 11 , no. 1 ( 2021 ): 10883 . 34035431 10.1038/s41598-021-90451-9 PMC8149845

41 Y. Yi and S. Ge , “ Targeting the Histone H3 Lysine 79 Methyltransferase DOT1L in MLL‐Rearranged Leukemias ,” Journal of Hematology & Oncology 15 , no. 1 ( 2022 ): 35 . 35331314 10.1186/s13045-022-01251-1 PMC8944089

42 J. Zhang , X. Gao , and L. Yu , “ Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins ,” Frontiers in Oncology 11 ( 2021 ): 741746 . 34540702 10.3389/fonc.2021.741746 PMC8440836

43 J. Yao , G. Li , Z. Cui , et al., “ The Histone Deacetylase Inhibitor I1 Induces Differentiation of Acute Leukemia Cells With MLL Gene Rearrangements via Epigenetic Modification ,” Frontiers in Pharmacology 13 ( 2022 ): 876076 . 35571127 10.3389/fphar.2022.876076 PMC9091196

44 G. M. Matthews , P. Mehdipour , L. A. Cluse , et al., “ Functional‐Genetic Dissection of HDAC Dependencies in Mouse Lymphoid and Myeloid Malignancies ,” Blood 126 , no. 21 ( 2015 ): 2392 – 2403 . 26447190 10.1182/blood-2015-03-632984 PMC4653767

45 M. Zhao , Y. Duan , J. Wang , et al., “ Histone Deacetylase Inhibitor I3 Induces the Differentiation of Acute Myeloid Leukemia Cells With t (8; 21) or MLL Gene Translocation and Leukemic Stem‐Like Cells ,” Journal of Oncology 2022 ( 2022 ): 3345536 . 36072977 10.1155/2022/3345536 PMC9441378

46 X. Ma , M. Zhao , Z. X. Wu , et al., “ The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem‐Like Cells ,” Frontiers in Oncology 12 ( 2022 ): 855570 . 35494054 10.3389/fonc.2022.855570 PMC9039182

47 C. Roolf , A. Richter , C. Konkolefski , et al., “ Decitabine Demonstrates Antileukemic Activity in B Cell Precursor Acute Lymphoblastic Leukemia With MLL Rearrangements ,” Journal of Hematology & Oncology 11 , no. 1 ( 2018 ): 62 . 29728108 10.1186/s13045-018-0607-3 PMC5936021

48 E. M. Stein , G. Garcia‐Manero , D. A. Rizzieri , et al., “ The DOT1L Inhibitor Pinometostat Reduces H3K79 Methylation and Has Modest Clinical Activity in Adult Acute Leukemia ,” Blood 131 , no. 24 ( 2018 ): 2661 – 2669 . 29724899 10.1182/blood-2017-12-818948 PMC6265654

49 O. Gilan , E. Y. Lam , I. Becher , et al., “ Functional Interdependence of BRD4 and DOT1L in MLL Leukemia ,” Nature Structural & Molecular Biology 23 , no. 7 ( 2016 ): 673 – 681 . 10.1038/nsmb.3249 27294782

50 C. W. Chen , R. P. Koche , A. U. Sinha , et al., “ DOT1L Inhibits SIRT1‐Mediated Epigenetic Silencing to Maintain Leukemic Gene Expression in MLL‐Rearranged Leukemia ,” Nature Medicine 21 , no. 4 ( 2015 ): 335 – 343 . 10.1038/nm.3832 PMC4390532 25822366

51 T. Abudureheman , J. Xia , M. H. Li , et al., “ CDK7 Inhibitor THZ1 Induces the Cell Apoptosis of B‐Cell Acute Lymphocytic Leukemia by Perturbing Cellular Metabolism ,” Frontiers in Oncology 11 ( 2021 ): 663360 . 33889549 10.3389/fonc.2021.663360 PMC8056175

52 C. Wang , H. Wang , C. Lieftink , et al., “ CDK12 Inhibition Mediates DNA Damage and Is Synergistic With Sorafenib Treatment in Hepatocellular Carcinoma ,” Gut 69 , no. 4 ( 2020 ): 727 – 736 . 31519701 10.1136/gutjnl-2019-318506

53 S. Zhang , R. Feng , J. Bai , et al., “ CDK7 Inhibition Induces Apoptosis in Acute Myeloid Leukemia Cells and Exerts Synergistic Antileukemic Effects With Azacitidine In Vitro and In Vivo ,” Leukemia & Lymphoma 64 , no. 3 ( 2023 ): 639 – 650 . 36657437 10.1080/10428194.2023.2169045

54 V. Juric , L. Hudson , J. Fay , et al., “ Transcriptional CDK Inhibitors, CYC065 and THZ1 Promote Bim‐Dependent Apoptosis in Primary and Recurrent GBM Through Cell Cycle Arrest and Mcl‐1 Downregulation ,” Cell Death & Disease 12 , no. 8 ( 2021 ): 763 . 34344865 10.1038/s41419-021-04050-7 PMC8333061

55 J. Ma , S. Zhao , X. Qiao , et al., “ Inhibition of Bcl‐2 Synergistically Enhances the Antileukemic Activity of Midostaurin and Gilteritinib in Preclinical Models of FLT3‐Mutated Acute Myeloid Leukemia ,” Clinical Cancer Research 25 , no. 22 ( 2019 ): 6815 – 6826 . 31320594 10.1158/1078-0432.CCR-19-0832 PMC6858954

56 J. Kołodrubiec , M. Kozłowska , N. Irga‐Jaworska , et al., “ Efficacy of Ruxolitinib in Acute Lymphoblastic Leukemia: A Systematic Review ,” Leukemia Research 121 ( 2022 ): 106925 . 35939887 10.1016/j.leukres.2022.106925

57 G. Krause , F. Hassenrück , and M. Hallek , “ Copanlisib for Treatment of B‐Cell Malignancies: The Development of a PI3K Inhibitor With Considerable Differences to Idelalisib ,” Drug Design, Development and Therapy 12 ( 2018 ): 2577 – 2590 . 30174412 10.2147/DDDT.S142406 PMC6109662

58 M. M. Dzama , M. Steiner , J. Rausch , et al., “ Synergistic Targeting of FLT3 Mutations in AML via Combined Menin‐MLL and FLT3 Inhibition ,” Blood 136 , no. 21 ( 2020 ): 2442 – 2456 . 32589720 10.1182/blood.2020005037 PMC8215191

59 F. M. Uckun and S. Qazi , “ Tyrosine Kinases in KMT2A/MLL‐Rearranged Acute Leukemias as Potential Therapeutic Targets to Overcome Cancer Drug Resistance ,” Cancer Drug Resist 5 , no. 4 ( 2022 ): 902 – 916 . 36627892 10.20517/cdr.2022.78 PMC9771742

60 S. M. Qi , J. Dong , Z. Y. Xu , X. D. Cheng , W. D. Zhang , and J. J. Qin , “ PROTAC: An Effective Targeted Protein Degradation Strategy for Cancer Therapy ,” Frontiers in Pharmacology 12 ( 2021 ): 692574 . 34025443 10.3389/fphar.2021.692574 PMC8138175

61 J. Velez , B. Dale , K. S. Park , H. Kaniskan , X. Yu , and J. Jin , “ Discovery of a Novel, Highly Potent EZH2 PROTAC Degrader for Targeting Non‐canonical Oncogenic Functions of EZH2 ,” European Journal of Medicinal Chemistry 267 ( 2024 ): 116154 . 38295690 10.1016/j.ejmech.2024.116154 PMC10901292

62 B. Zhou , Y. Qin , J. Zhou , et al., “ Bortezomib Suppresses Self‐Renewal and Leukemogenesis of Leukemia Stem Cell by NF‐ĸB‐Dependent Inhibition of CDK6 in MLL‐Rearranged Myeloid Leukemia ,” Journal of Cellular and Molecular Medicine 25 , no. 6 ( 2021 ): 3124 – 3135 . 33599085 10.1111/jcmm.16377 PMC7957264

63 K. M. Bernot , J. S. Nemer , R. Santhanam , et al., “ Eradicating Acute Myeloid Leukemia in a Mll(PTD/Wt):Flt3(ITD/Wt) Murine Model: A Path to Novel Therapeutic Approaches for Human Disease ,” Blood 122 , no. 23 ( 2013 ): 3778 – 3783 . 24085765 10.1182/blood-2013-06-507426 PMC3843236

64 L. C. Cheung , R. de Kraa , J. Oommen , et al., “ Preclinical Evaluation of Carfilzomib for Infant KMT2A‐Rearranged Acute Lymphoblastic Leukemia ,” Frontiers in Oncology 11 ( 2021 ): 631594 . 33937032 10.3389/fonc.2021.631594 PMC8082024

65 A. B. Leahy , K. J. Devine , Y. Li , et al., “ Impact of High‐Risk Cytogenetics on Outcomes for Children and Young Adults Receiving CD19‐Directed CAR T‐Cell Therapy ,” Blood 139 , no. 14 ( 2022 ): 2173 – 2185 . 34871373 10.1182/blood.2021012727 PMC8990372

66 N. J. Short , E. Jabbour , N. Jain , and H. Kantarjian , “ Inotuzumab Ozogamicin for the Treatment of Adult Acute Lymphoblastic Leukemia: Past Progress, Current Research and Future Directions ,” Journal of Hematology & Oncology 17 , no. 1 ( 2024 ): 32 . 38734670 10.1186/s13045-024-01552-7 PMC11088766

67 A. Lattupally , A. Lorenzana , G. A. Yanik , and D. Bell , “ Prolonged Remission in Multiple Relapsed MLL‐Rearranged Infant B‐ALL With Inotuzumab Ozogamicin ,” Pediatric Blood & Cancer 70 , no. 4 ( 2023 ): e30055 . 36266959 10.1002/pbc.30055

68 A. B. Leahy , H. Newman , Y. Li , et al., “ CD19‐Targeted Chimeric Antigen Receptor T‐Cell Therapy for CNS Relapsed or Refractory Acute Lymphocytic Leukaemia: A Post‐Hoc Analysis of Pooled Data From Five Clinical Trials ,” Lancet Haematol 8 , no. 10 ( 2021 ): e711 – e722 . 34560014 10.1016/S2352-3026(21)00238-6 PMC9026766

69 M. Rose , J. T. Burgess , K. O'Byrne , D. J. Richard , and E. Bolderson , “ PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance ,” Frontiers in Cell and Development Biology 8 ( 2020 ): 564601 . 10.3389/fcell.2020.564601 PMC7509090 33015058

70 A. Padella , A. Ghelli Luserna Di Rorà , G. Marconi , M. Ghetti , G. Martinelli , and G. Simonetti , “ Targeting PARP Proteins in Acute Leukemia: DNA Damage Response Inhibition and Therapeutic Strategies ,” Journal of Hematology & Oncology 15 , no. 1 ( 2022 ): 10 . 35065680 10.1186/s13045-022-01228-0 PMC8783444

71 L. Zhao and C. W. E. So , “ PARPi Potentiates With Current Conventional Therapy in MLL Leukemia ,” Cell Cycle 16 , no. 20 ( 2017 ): 1861 – 1869 . 28886273 10.1080/15384101.2017.1288325 PMC5638355

72 M. T. Esposito , L. Zhao , T. K. Fung , et al., “ Synthetic Lethal Targeting of Oncogenic Transcription Factors in Acute Leukemia by PARP Inhibitors ,” Nature Medicine 21 , no. 12 ( 2015 ): 1481 – 1490 . 10.1038/nm.3993 26594843

73 J. Piao , S. Takai , T. Kamiya , et al., “ Poly (ADP‐Ribose) Polymerase Inhibitors Selectively Induce Cytotoxicity in TCF3‐HLF‐Positive Leukemic Cells ,” Cancer Letters 386 ( 2017 ): 131 – 140 . 27894958 10.1016/j.canlet.2016.11.021

74 H. Z. Qi , N. Xu , J. Xu , et al., “ Allogeneic Hematopoietic Stem Cell Transplantation Overcomes the Poor Prognosis in MLL‐Rearranged Solid Tumor Therapy Related‐Acute Myeloid Leukemia ,” American Journal of Cancer Research 11 , no. 4 ( 2021 ): 1683 – 1696 . 33948382 PMC8085874

75 H. Yang , S. Huang , C. Y. Zhu , et al., “ The Superiority of Allogeneic Hematopoietic Stem Cell Transplantation Over Chemotherapy Alone in the Treatment of Acute Myeloid Leukemia Patients With Mixed Lineage Leukemia (MLL) Rearrangements ,” Medical Science Monitor 22 ( 2016 ): 2315 – 2323 . 27373985 10.12659/MSM.899186 PMC4941891

76 T. Edahiro , H. Ureshino , R. Chishaki , et al., “ Successful Combination Treatment With Azacitidine and Venetoclax as a Bridging Therapy for Third Allogenic Stem Cell Transplantation in a Patient With 11q23/MLL‐Rearranged Complex Karyotype Acute Myeloid Leukemia ,” EJHaem 4 , no. 1 ( 2023 ): 273 – 275 . 36819153 10.1002/jha2.630 PMC9928651

77 X. Y. Cao , J. Q. Chen , H. Wang , et al., “ Addition of Venetoclax to Myeloablative Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in High‐Risk AML ,” Annals of Medicine 55 , no. 1 ( 2023 ): 388 – 400 . 36629738 10.1080/07853890.2022.2164610 PMC9851264

78 G. C. Issa , F. Ravandi , C. D. DiNardo , E. Jabbour , H. M. Kantarjian , and M. Andreeff , “ Therapeutic Implications of Menin Inhibition in Acute Leukemias ,” Leukemia 35 , no. 9 ( 2021 ): 2482 – 2495 . 34131281 10.1038/s41375-021-01309-y

79 B. Falini , L. Brunetti , P. Sportoletti , and M. P. Martelli , “ NPM1‐Mutated Acute Myeloid Leukemia: From Bench to Bedside ,” Blood 136 , no. 15 ( 2020 ): 1707 – 1721 . 32609823 10.1182/blood.2019004226

80 W. C. M. Dempke , M. Desole , P. Chiusolo , S. Sica , and M. Schmidt‐Hieber , “ Targeting the Undruggable: Menin Inhibitors Ante Portas ,” Journal of Cancer Research and Clinical Oncology 149 , no. 11 ( 2023 ): 9451 – 9459 . 37103568 10.1007/s00432-023-04752-9 PMC11798168

81 D. Tomizawa , T. Miyamura , T. Imamura , et al., “ A Risk‐Stratified Therapy for Infants With Acute Lymphoblastic Leukemia: A Report From the JPLSG MLL‐10 Trial ,” Blood 136 , no. 16 ( 2020 ): 1813 – 1823 . 2022. Blood 139, no. 18: 2848. 32845001 10.1182/blood.2019004741

82 R. Pieters , P. De Lorenzo , P. Ancliffe , et al., “ Outcome of Infants Younger Than 1 Year With Acute Lymphoblastic Leukemia Treated With the Interfant‐06 Protocol: Results From an International Phase III Randomized Study ,” Journal of Clinical Oncology 37 , no. 25 ( 2019 ): 2246 – 2256 . 31283407 10.1200/JCO.19.00261