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Efficacy of tyrosine kinase inhibitors on a mouse chronic myeloid leukemia model and chronic myeloid leukemia stem cells.

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder caused by constitutively active BCR-ABL1 tyrosine kinase resulting from the t(9;22) Philadelphia translocation. Imatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI), is a revolutionary molecular target inhibitor for CML. However, leukemic stem cells (LSCs) eventually become resistant to imatinib and thereby cause relapse. The next-generation BCR-ABL1 TKI dasatinib is also unable to eliminate CML LSCs. On the other hand, the third-generation BCR-ABL1 TKI ponatinib is not well studied in terms of its efficacy on CML LSCs. Here,

Siwu decoction suppress myeloid-derived suppressor cells through tumour cells necroptosis to inhibit hepatocellular carcinoma.

BACKGROUND: Human hepatocellular carcinoma (HCC) acquired resistance to anti-cancer agents due to the presence of immunosuppressive tumour microenvironment (TME) established by the interaction between tumour cells and immune populations. New treatment targeting the interaction is urgently needed and clinically beneficial to patients with HCC. This study aims to explore the anti-tumour effect of a Traditional Chinese Medicine formula Siwu Decoction (SWD) and its potential mechanism. MATERIALS AND METHODS: The chemical profile of SWD was determined by high-performance liquid chromatography coup

T cells and monocyte-derived myeloid cells mediate immunotherapy-related hepatitis in a mouse model.

BACKGROUND & AIMS: Immune checkpoint inhibitors (ICIs) are associated with immune-related adverse events (irAEs) which are more severe when ICIs are used in combination. We aimed to use a mouse model to elucidate the molecular mechanisms of immune-related hepatitis, one of the common irAEs associated with ICIs. METHODS: Immune phenotyping and molecular profiling were performed on Pdcd1-/- mice treated with anti-CTLA4 and/or the IDO1 inhibitor epacadostat or a 4-1BB agonistic antibody. RESULTS: ICI combination-induced hepatitis and 4-1BB agonist-mediated hepatitis share similar features yet m

Induced pluripotent stem cells-derived myeloid-derived suppressor cells regulate the CD8+ T cell response.

Myeloid-derived suppressor cells (MDSCs) are markedly increased in cancer patients and tumor-bearing mice and promote tumor growth and survival by inhibiting host innate and adaptive immunity. In this study, we generated and characterized MDSCs from murine-induced pluripotent stem cells (iPSCs). The iPSCs were co-cultured with OP9 cells, stimulated with GM-CSF, and became morphologically heterologous under co-culturing with hepatic stellate cells. Allogeneic and OVA-specific antigen stimulation demonstrated that iPS-MDSCs have a T-cell regulatory function. Furthermore, a popliteal lymph node a

Discovery of survival factor for primitive chronic myeloid leukemia cells using induced pluripotent stem cells.

A definitive cure for chronic myeloid leukemia (CML) requires identifying novel therapeutic targets to eradicate leukemia stem cells (LSCs). However, the rarity of LSCs within the primitive hematopoietic cell compartment remains a major limiting factor for their study in humans. Here we show that primitive hematopoietic cells with typical LSC features, including adhesion defect, increased long-term survival and proliferation, and innate resistance to tyrosine kinase inhibitor (TKI) imatinib, can be generated de novo from reprogrammed primary CML cells. Using CML iPSC-derived primitive leukemia

Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-γ.

Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia arising from the oncogenic break point cluster region/Abelson murine leukemia viral oncogene homolog 1 translocation in hematopoietic stem cells (HSCs), resulting in a leukemia stem cell (LSC). Curing CML depends on the eradication of LSCs. Unfortunately, LSCs are resistant to current treatment strategies. The host's immune system is thought to contribute to disease control, and several immunotherapy strategies are under investigation. However, the interaction of the immune system with LSCs is poorly defined. In the presen

Global dynamics of hematopoietic stem cells and differentiated cells in a chronic myeloid leukemia model.

We consider a mathematical model describing evolution of normal and leukemic hematopoietic stem cells (HSC) and differentiated cells in bone marrow. We focus on chronic myeloid leukemia (CML), a cancer of blood cells resulting from a malignant transformation of hematopoietic stem cells. The dynamics are given by a system of ordinary differential equations for normal and leukemic cells. Homeostasis regulates the proliferation of normal HSC and leads the dynamics to an equilibrium. This mechanism is partially efficient for leukemic cells. We define homeostasis by a functional of either hematopoi

Influence of human bone marrow mesenchymal stem cells on proliferation of chronic myeloid leukemia cells.

BACKGROUND AND OBJECTIVE: Bone marrow mesenchymal stem cells (MSCs) are of particular interest due their potential clinical use in tissue engineering. MSCs could secret soluble factor(s) upon stimulation. This study was to evaluate the influence of human bone marrow MSCs on proliferation of chronic myeloid leukemia cells, and assess the secretion of cytokines in the supernatant induced by MSCs. METHODS: Bone marrow MSCs extracted from healthy donors were cultured in DMEM-LG. The surface markers on the third passage MSCs were detected by flow cytometry. MSCs were co-cultured with chronic myelo

Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells.

We showed previously that hyperforin (HF), a natural phloroglucinol, stimulated apoptosis in B cell chronic lymphocytic leukaemia cells (CLL) and displayed anti-angiogenic properties. In the present work, we investigated the effects of hyperforin on the activity of P-gp/MDR1, an ABC (ATP-binding cassette) transporter putatively involved in multidrug resistance (MDR). Ex vivo treatment of CLL cells with HF markedly impaired the activity of P-gp, as measured by the inhibition of the capacity of the treated cells to efflux the rhodamine 123 probe. In addition, most CLL cells expressed breast canc

Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells.

Dendritic cells (DCs) are essential antigen-presenting cells for the induction of T cell immunity against pathogens such as human immunodeficiency virus (HIV)-1. At the same time, HIV-1 replication is strongly enhanced in DC-T cell clusters, potentially undermining this process. We found that immature CD123(+) plasmacytoid DCs (PDCs) and CD11c(+) myeloid DCs (MDCs) were susceptible to both a CCR5- and a CXCR4-using HIV-1 isolate in vitro and were able to efficiently transfer that infection to autologous CD4(+) T cells. Soon after HIV-1 exposure, both PDCs and MDCs were able to transfer the vir

Generation of dendritic cells expressing bcr-abl from CD34-positive chronic myeloid leukemia precursor cells.

Patients with a relapse of chronic myeloid leukemia (CML) after allogeneic bone marrow transplantation can be successfully treated with blood mononuclear cells from the original bone marrow donor. However, the antileukemic effect of this treatment is often accompanied by graft-versus-host disease (GVHD). Treatment with cytotoxic T-lymphocyte (CTL) lines or clones that are specifically generated against leukemic antigen-presenting cells from the patient, may separate antileukemic effects from GVHD. In this report we demonstrate that after culturing CD34-positive cells purified from bone marrow

Granulocytic and Monocytic Myeloid-Derived Suppressor Cells are Functionally and Prognostically Different in Patients with Chronic Myeloid Leukemia.

Myeloid-derived suppressor cells (MDSCs) represent phenotypically heterogeneous populations that suppress tumor-specific T-cell responses. MDSCs are produced from myeloid precursors in emergent states and are increased in several hematologic malignancies. We evaluated the differences in the levels and prognostic significance of MDSCs according to the clinical status of chronic myeloid leukemia (CML). The percentages and numbers of granulocytic (g)MDSCs and monocytic (m)MDSCs in peripheral blood (PB) and bone marrow (BM) aspirates were determined by five-color flow cytometry (HLA-DR/CD11b/CD15/

Effect of myeloid-derived suppressor cells on retinal epithelial cells in retinopathy of prematurity model.

BACKGROUND: Retinopathy of prematurity (ROP) is a proliferative vascular disease with a high incidence rate. Myeloid-derived suppressor cells (MDSCs) are a type of stem cell that possesses remarkable regenerative and reparative capabilities. However, the role of MDSCs as a stem cell therapy in the treatment of ROP remains unclear. Therefore, this study aimed to explore the effects of MDSC therapy on the expression of glial fibrillary acidic protein (GFAP) and vascular endothelial growth factor (VEGF) in a model of ROP, thereby preliminarily assessing the therapeutic potential of MDSCs in ROP.

Mesenchymal Stem Cells and Myeloid-Derived Suppressor Cells Interplay in Adjuvant-Induced Arthritis Rat Model.

There has not been much researchs on the biological relationship between myeloid-derived suppressor cells (MDSCs) and mesenchymal stem cells (MSCs). The goal of the current work is to examine how these cells cooperate with one another in a rat model of adjuvant-induced arthritis (AIA). Three groups of equal numbers of rats were created; the first group served as the control. Complete Freund's adjuvant (CFA) was injected into the second group to induce AIA. The third group underwent MSCstreatment. Three weeks later, ANA, IL-1β, IL-4, IL-6, IL-10, TNF-α, IFN-γ, M-CSF, iNOS and Arg-1 were determi

Granulocytic myeloid-derived suppressor cells inhibit T follicular helper cells during experimental Schistosoma japonicum infection.

BACKGROUND: CD4+ T helper (Th) cells play critical roles in both host humoral and cellular immunity against parasitic infection and in the immunopathology of schistosomiasis. T follicular helper (Tfh) cells are a specialized subset of Th cells involved in immunity against infectious diseases. However, the role of Tfh cells in schistosome infection is not fully understood. In this study, the dynamics and roles of Tfh cell regulation were examined. We demonstrated that granulocytic myeloid-derived suppressor cells (G-MDSC) can suppress the proliferation of Tfh cells. METHODS: The levels of Tfh

CD45dimCD34+CD38-CD133+ cells have the potential as leukemic stem cells in acute myeloid leukemia.

BackgroundLeukemia stem cells (LSCs) in play an important role in the initiation, relapse, and progression of acute myeloid leukemia (AML), and in the development of chemotherapeutic drug resistance in AML. Studies regarding the detection of LSCs and the development of novel therapies for targeting them are extensive. The identification of LSCs and targeting therapies for them has been continuously under investigation.MethodsWe examined the levels of CD45dimCD34+CD38-CD133+ cells in bone marrow samples from patients with hematological malignancies and healthy controls, using four-color flow cy

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… Reikvam H Brenner AK Hagen KM Liseth K Skrede S Hatfield KJ Bruserud O The cytokine-mediated crosstalk between primary human acute myeloid cells and mesenchymal stem cells alters the local cytokine network and the global gene expression profile of the mesenchymal cells Stem Cell Res 2015 15 530 541 10.1016 …

Levels and Clinical Significance of Regulatory B Cells and T Cells in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy, whose immunological mechanisms are still partially uncovered. Regulatory B cells (Bregs) and CD4+ regulatory T cells (Tregs) are subgroups of immunoregulatory cells involved in modulating autoimmunity, inflammation, and transplantation reactions. Herein, by studying the number and function of Breg and Treg cell subsets in patients with AML, we explored their potential role in the pathogenesis of AML. Newly diagnosed AML patients, AML patients in complete remission, and healthy controls were enrolled. Flow cytometry was u

Zika virus infection differentially affects genome-wide transcription in neuronal cells and myeloid dendritic cells.

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus that has attracted global attention and international awareness. ZIKV infection exhibits mild symptoms including fever and pains; however, ZIKV has recently been shown to be related to increased birth defects, including microcephaly, in infants. In addition, ZIKV is related to the onset of neurological disorders, such as a type of paralysis similar to Guillain-Barré syndrome. However, the mechanisms through which ZIKV affect neuronal cells and myeloid dendritic cells and how ZIKV avoids host immunity are unclear. Accordingly, in this s

Comparison of chronic myeloid leukemia stem cells and hematopoietic stem cells by global proteomic analysis.

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the standard first-line therapy for patients with chronic-phase CML. However, TKIs cannot eliminate quiescent leukemia stem cells (LSCs) which persist in all patients on long-term therapy and provides a reservoir for disease progression and recurrence. Many researches have confirmed that TKI-resistant LSCs compartment can be captured within CD26 + fraction. In order to analyze distinctive biological characteristics of TKI-resistant LSCs, we isolated the CD34 + CD38-CD26+, CD34 + CD38-CD26-and CD34 + CD38 + cells from 8 CML patients util

Chronic myeloid leukemia lysate-loaded dendritic cells induce T-cell responses towards leukemia progenitor cells.

Treatment of chronic myeloid leukemia with tyrosine kinase inhibitors, such as imatinib mesylate, dasatinib and nilotinib, results in high rates of cytogenetic and molecular responses. However, in many patients, minimal residual disease is detected by molecular techniques. Since chronic myeloid leukemia cells are particularly good targets for immune surveillance mechanisms, we explored active specific immunotherapy using leukemia lysate-loaded dendritic cells in vitro. Our data show the potency of dendritic cell-based vaccination strategies for the induction of T cell-mediated responses to era