NEAT1 lncRNA overexpression results in short-term progression and poor treatment outcome in childhood B-ALL.

INTRODUCTION

Leukaemia is the most commonly diagnosed cancer in children and adolescents, comprising approximately 33% of childhood malignancies in individuals under 15 years old. 1 , 2 The vast majority of cases are acute and are classified as either acute lymphoblastic leukaemia (ALL) or acute myeloid leukaemia (AML), based on their lymphoid or myeloid stem cell origin. Among these, B‐cell ALL (B‐ALL) is the most common subtype, comprising approximately 70%–75% of newly diagnosed cases. 3 Childhood B‐ALL (chB‐ALL) management is considered as one of the success stories in modern clinical oncology, leading to impressive 5‐year relapse‐free and overall survival rates ≥85%. 3 , 4 Nevertheless, approximately 20% of patients experience treatment resistance or relapse, while interestingly ~35% of these cases involve patients initially classified as having a favourable prognosis (standard risk). 5 At the same time, ALL treatment is related to acute and long‐term toxicities, negatively impacting patients' quality of life. 6 In this regard, addressing treatment failure, improving risk stratification and providing personalized prognosis and treatment decisions remain major clinical challenges.

Although the precise aetiology remains largely unknown, leukaemia is fundamentally considered as a genetic disease. Numerous chromosomal and genetic abnormalities have been described to drive tumorigenesis and progression of childhood leukaemia, as well as to provide prognostic information and influence clinical management. 7 , 8 However, the current knowledge cannot fully interpret the molecular landscape of leukaemogenesis and progression as well as the heterogeneity regarding treatment responses. According to the ENCODE project, only 2% of the genome consists of protein‐coding genes, while >75% is actively transcribed into non‐coding RNAs (ncRNAs). 9 , 10 ncRNAs have emerged as the most potent regulators of gene expression, playing key roles in normal cellular homeostasis, 11 , 12 and numerous human diseases, including cancer. 13 , 14 , 15 , 16 , 17 Long non‐coding RNAs (lncRNAs) are single‐stranded regulatory RNAs >200 nt, capable of modulating gene expression at epigenetic, transcriptional and post‐transcriptional levels. 18 , 19 , 20 Specifically, lncRNAs function as guides or scaffolds, recruiting chromatin‐modifying complexes and transcription factors/repressors to target genomic loci, as well as splicing protein complexes and mRNA decay mediators to target transcripts. Moreover, lncRNAs act as molecular decoys by sponging tumour‐related miRNAs and regulating their bioavailability. 20 , 21 , 22

Nuclear Enriched Abundant Transcript 1 (NEAT1) is a single exon, intergenic lncRNA that is transcribed by RNA polymerase II from the NEAT1 gene in the familial tumour syndrome multiple endocrine neoplasia type 1 (MEN1) locus on 11q13.1. NEAT1 was first discovered in 2007 by Hutchinson et al. as a massively abundant and essential structural scaffold of nuclear paraspeckles. 23 , 24 , 25 , 26 , 27 The expression of the NEAT1 gene locus produces two transcripts, the short NEAT1_1 (3.7 kb) and the long NEAT1_2 (22.7 kb) isoforms, that share the same transcriptional start site; however, they undergo altered 3′‐end processing. 23 , 28 The shorter NEAT1_1 transcripts result from canonical RNA processing and 3′‐end polyadenylation, while the longer NEAT1_2 isoform undergoes non‐canonical processing by RNases P and Z at the 3′‐end, resulting in a triple‐helix tRNA‐like structure that stabilizes the transcript and protects it from degradation. 28 , 29 , 30 Of the two isoforms, only NEAT1_2 acts as an essential component of paraspeckles, while the shorter NEAT1_1 transcript is not a major component, is implicated in paraspeckle‐independent cellular functions 24 , 29 , 31 and is significantly overexpressed compared to the NEAT1_2 transcript. 23 , 32

Currently, numerous studies have highlighted the deregulated expression and the prognostic utility of NEAT1 in human malignancies. However, NEAT1's role and clinical value in childhood ALL remain unknown. Herein, we have examined the NEAT1 expression profile in chB‐ALL patients and healthy children, and we analysed for the first time NEAT1's clinical utility for the prognosis, risk stratification and prediction of treatment outcome of chB‐ALL patients.

MATERIALS AND METHODS

Detailed materials and methods are provided in Supplemental Information.

Screening cohort

The study cohort consisted of 160 children with B‐cell precursor ALL and 68 age‐matched children not suffering from any haematological or other type of malignancy as normal controls. Patients were diagnosed between May 2006 and April 2020 at the Oncology Department of ‘P. & A. Kyriakou’ Children's Hospital, Athens, Greece, and treated according to the BFM backbone protocols. A total of 336 bone marrow (BM) samples were analysed in the study. BM specimens were obtained by aspiration from all B‐ALL patients at the time of diagnosis ( n = 160), while matched BM samples at the end of induction (EoI; day 33) were available from 108 patients in the screening cohort and were included without selection bias. Finally, BM samples from 68 healthy age‐matched and treatment‐free children, not suffering from any haematological or other type of malignancy, were obtained by the same Institution (Oncology Dept., ‘P. & A. Kyriakou’ Children's Hospital) simultaneously with patients' samples and analysed as controls.

Cytogenetics

Cytogenetic analysis was performed by direct preparation of unstimulated BM cells, followed by 24‐h culture in RPMI 1540 culture medium with 25% fetal calf serum at 37°C. The standard G‐banding technique was employed for metaphase chromosome analysis, and classification was performed according to the International System for Cytogenetic Nomenclature (ISCN).

Immunohistotype analysis

Multiparametric flow cytometry using direct immunofluorescence was conducted for the immunohistotype analysis of BM aspirates on an FC‐500 cytometer (Beckman Coulter Inc., Nyon, Switzerland) with CXP software.

Minimal residual disease (MRD) evaluation

Minimal residual disease (MRD) was assessed on days 15 (MRD 15 ) and 33 (MRD 33 ) of induction treatment by multiparametric flow cytometry on an FC‐500 cytometer (Beckman Coulter Inc.) according to BFM protocol guidelines. A cut‐off value of 0.01% was used for the interpretation of an MRD result as positive.

Total RNA extraction and first‐strand cDNA synthesis

Total RNA was isolated from BM aspirates using TRI‐Reagent BD (Molecular Research Centre, Inc., Cincinnati, OH, USA) and reversed transcribed as previously described. 33 , 34

Quantitative real‐time PCR (qPCR)

NEAT1 expression was quantified by quantitative real‐time PCR (qPCR), using the 2 −ΔΔCT relative quantification method and GAPDH as the endogenous reference control for normalization.

Statistical analysis

Non‐parametric tests were applied accordingly to assess the correlation between NEAT1 levels and categorical variables. Survival analysis of the patients was conducted using Kaplan–Meier survival curves and Cox proportional regression analysis. Relapse and death served as clinical end‐points. The X‐tile algorithm was used for the adoption of the optimal cut‐off values of the NEAT1 levels in B‐ALL patients. Bootstrap analysis based on 1000 bootstrap samples was conducted for internal validation of Cox regression models. Finally, decision curve analysis according to Vickers et al. 35 was applied to assess the clinical benefit of the NEAT1‐fitted multivariate models on patients' prognosis and treatment response.

RESULTS

Baseline clinical and experimental data

Of the 160 enrolled B‐ALL patients, four were excluded from analysis due to a BM blast percentage <80% at diagnosis. Additionally, two specimens from B‐ALL patients and three from the control group were excluded due to low RNA quality. As a result, the patients' cohort included 154 children with B‐ALL (96.1% CD10+), with a median age of 5.0 years (mean ± SE: 6.61 ± 0.34 years), and the controls' cohort ( n = 65) with a median age also of 5.0 years (mean ± SE: 5.93 ± 0.53 years). Most of the enrolled patients were male (55.8%), with white blood cells (WBC) <20 000/μL (66.2%) and a median %BM blast of 95.0% at diagnosis. ETV6‐RUNX1/t(12;21)(p13;q22) translocation and high hyperdiploidy (>50 chromosomes) were detected in 26.0% and 15.6% respectively. Poor prednisone response on day 8 (≥1000 blasts/mL) and M2/3 BM response (≥5% blasts) on day 15 were reported in 7.1% ( n = 11) and 17.5% ( n = 27) respectively. MRD 15 and MRD 33 data were available for 127 (82.5%) and 111 (72.1%) patients, with 94 (74.0%) and 20 (18.0%) testing positive (≥0.01%) respectively. Based on BFM guidelines, 20 (13.0%), 108 (70.1%) and 26 (16.9%) patients were finally stratified as standard, intermediate and high/very high risk respectively. Matched BM samples at the EoI were available from 108 patients of the screening cohort and were included in the study without selection bias. The analysis of clinicopathological data of the diagnosis ( n = 154) and the EoI ( n = 108) did not highlight any statistically significant differences (Table S1 ).

The median follow‐up time was 10.3 years (123.0 months). During follow‐up, 17 patients (11.0%) experienced relapse, whereas 15 patients died (9.7%), displaying mean disease‐free survival (DFS) and overall survival (OS) of 182.3 months (95% CI: 173.0–191.6) and 184.6 months (95% CI: 175.8–193.5) respectively. The flow diagram of the study is included in Figure 1 , while patients' clinical data are presented in Table 1 .

NEAT1 overexpression at B‐ALL diagnosis is associated with a significantly higher risk for short‐term progression and a poor treatment response

The analysis of NEAT1 levels in BM aspirates did not reveal any significant differences between B‐ALL patients and healthy controls, nor between diagnosis and EoI (Figure S1 ). Relapse or death (whichever was recorded first) was used as the clinical end‐points for the OS and progression‐free survival (PFS). Using the X‐tile algorithm, the median of NEAT1 levels at diagnosis was adopted as the optimal cut‐off value for the patients' classification. NEAT1 expression (categorical) showed no significant association with most clinicopathological or treatment response data (Table 1 ), other than MRD 33 ≥ 0.01% ( p = 0.045) and patients' mortality ( p = 0.027). Moreover, B‐ALL patients with MRD 33 ≥ 0.01% displayed significantly higher NEAT1 levels (continuous) at disease diagnosis ( p = 0.023; Figure 2 ).

The survival analysis (Figure 2 ) clearly demonstrated that patients with NEAT1 overexpression at diagnosis had significantly poorer prognoses and treatment outcomes. Specifically, Kaplan–Meier curves revealed poorer PFS ( p = 0.039; Figure 2B ) and OS ( p = 0.018; Figure 2C ) of the ‘NEAT1‐high’ patients compared with those having moderate/low NEAT1 expression. Patients' survival analysis comparing the lowest (first) and highest (third) tertiles of NEAT1 expression at diagnosis is presented in Figure S2 . Moreover, the univariate Cox regression analysis (Figure 3 ) confirmed that B‐ALL children with increased NEAT1 levels at diagnosis had a significantly higher risk of short‐term progression (HR = 2.471; 95% CI: 1.016–6.010; p = 0.035) and death (HR = 4.078; 95% CI: 1.150–14.46; p = 0.015) compared to the ‘NEAT1‐low’ subgroup.

Multivariate Cox regression analysis (Figure 3 ) was performed to assess the independent prognostic value of NEAT1 levels at diagnosis for B‐ALL treatment outcomes. Multivariate models were adjusted for the clinically established disease prognostic markers according to the ALL IC‐BFM 2009 guidelines, including WBC, prednisone response, BM response on day 15, MRD 15 , ALL IC‐BFM risk group and age at diagnosis, while bootstrap analysis was performed for internal validation of the models. The multivariate analysis documented the independent clinical value of NEAT1 overexpression for the progression (HR = 2.957; 95% CI: 1.122–7.790; p = 0.011) and the poor survival (HR = 5.832; 95% CI: 1.259–27.01; p = 0.012) of the children with B‐ALL following treatment.

NEAT1 evaluation improves the prognostic strength of the B‐ALL clinical used markers

Given the independent clinical utility of NEAT1 levels at diagnosis, we evaluated its potential to enhance the predictive power of established and routinely used B‐ALL clinical markers. According to the ALL IC‐BFM 2009 guidelines, WBC at diagnosis, prednisone response on day 8, BM response on day 15 and MRD 15 represent the main markers for patients' prognosis and treatment decisions.

The survival analysis (Figure 4 ) clearly demonstrated the superior risk stratification of the patients by the assessment of NEAT1 levels along with the clinically used markers. Specifically, children overexpressing NEAT1 at diagnosis had a significantly higher risk for short‐term disease progression and poor survival rates regardless of WBC < 20 000 cells/μL (PFS: p = 0.016, Figure 4A ; OS: p = 0.015, Figure 4B ) or M1 response at day 15 (PFS: p = 0.003, Figure 4C ; OS: p = 0.015, Figure 4D ). More precisely, NEAT1 evaluation resulted in a higher positive predictive value (PPV) of 26.0% for PFS (Figure 4A ) and 20.0% for OS (Figure 4B ) of the WBC < 20 000/μL patients overexpressing NEAT1 compared to 15.7% and 11.8% of the WBC < 20 000/μL baseline subgroup, respectively. Moreover, 16.4% for PFS (Figure 4C ) and 11.5% for OS (Figure 4D ) PPV was highlighted for M1 patients with NEAT1 overexpression compared to 11.0% and 7.1% of the M1 baseline group. Moreover, NEAT1 levels at diagnosis significantly enhanced the prognostic strength of MRD 15 . More precisely, among patients with MRD 15 ≥ 0.1%, those overexpressing NEAT1 had significantly worse PFS ( p = 0.013; Figure 4E ) and OS ( p = 0.006; Figure 4F ) compared to the ‘NEAT1‐low’ MRD 15 ≥ 0.1% subgroup, which resembled the prognosis and outcomes of MRD 15 < 0.1% patients. In this regard, NEAT1 evaluation resulted in significantly improved PPV of 30.8% for PFS (Figure 4E ) and 23.1% for OS (Figure 4F ) of ‘NEAT1‐high’ MRD 15 ≥ 0.1% subgroup compared to 18.8% and 11.8% of the MRD 15 ≥ 0.1% baseline group.

Decision curve analysis of NEAT1‐fitted multivariate models for B‐ALL prognosis

To evaluate the clinical benefit of the NEAT1‐fitted multivariate models for the prognosis and treatment outcome of the patients, we performed decision curve analysis (Figure 5 ). The analysis clearly demonstrated the improved clinical net benefit of the multivariate models fitted for NEAT1 levels at diagnosis for both the disease progression (PFS; Figure 5A ) and patients' survival (OS; Figure 5B ) compared to the control model of ALL IC‐BFM risk group of the patients, from low threshold probabilities <10%.

DISCUSSION

Childhood ALL clinical management relies on patients' risk stratification and risk‐adjusted chemotherapy schemes and has resulted in substantially increased remission rates and survival benefit. However, there are still major clinical concerns, as 15%–20% of the children will develop resistance to chemotherapy and relapse.

In recent years, numerous studies have documented the active involvement of lncRNAs in leukaemogenesis and disease courses, as well as their clinical ability to support modern molecular diagnostics/prognostics and precision medicine in paediatric leukaemia. 33 , 36 , 37 Despite many recent studies that have highlighted the frequent deregulation and the clinical value of NEAT1 lncRNA in numerous solid and haematological human malignancies, its impact in childhood ALL has not been explored yet. In the present study, we have performed an expression analysis of the NEAT1_1 lncRNA isoform in BM blasts of chB‐ALL patients at diagnosis and EoI as well as healthy controls, and we evaluated its clinical utility in disease prognosis and patients' treatment outcome. Our findings showed that NEAT1 levels did not differ significantly between B‐ALL patients and healthy controls, nor between diagnosis and EoI. However, patients' survival analysis highlighted the association of NEAT1 overexpression at diagnosis with significantly higher risk for relapse and worse survival. Interestingly, multivariate Cox models documented the superior value of NEAT1 levels to predict post‐treatment patients' relapse and survival independently of the established and clinically used prognostic markers.

This independent prognostic value was further confirmed by the ability of NEAT1 levels to improve the prognostic utility of the established and routinely used markers of MRD, BM morphology and WBC. More precisely, NEAT1‐fitted multivariate models could effectively identify B‐ALL patients at higher risk for relapse and poor OS, despite <20 000 WBC/μL at diagnosis or the favourable M1 response to BFM backbone protocol (day 15). Similarly, evaluation of NEAT1 levels significantly improves risk stratification of MRD 15 ≥ 0.1% subgroup, as ‘NEAT1‐high’ children displayed worse PFS and OS compared with the favourable treatment outcome of ‘NEAT1‐low’ MRD 15 ≥ 0.1% subgroup, which resembled the prognosis of MRD 15 < 0.1% group. Finally, decision curve analysis clearly confirmed the superior prognostic value of the NEAT1‐fitted multivariate models and the clinical benefit for childhood ALL risk stratification and prognostication compared to the ‘control’ model of the routinely used disease markers.

The association of NEAT1_1 overexpression with a higher risk for poor outcomes of the chB‐ALL patients is in line with previous studies. Elevated NEAT1 lncRNA levels have been reported in the vast majority of solid tumours compared to normal counterparts, including, among others, prostate, breast, colorectal, lung, hepatocellular, gastric and ovarian cancers, correlating also with disease progression and worse prognosis. 38 , 39 , 40 , 41 Indeed, a growing body of evidence has demonstrated that NEAT1 lncRNA favours cancer cell proliferation and survival, enhances cancer stem cell properties and epithelial‐to‐mesenchymal transition and inhibits apoptosis, mostly by acting as competitive endogenous RNA (ceRNA) and sponging tumour‐suppressor miRNAs. 42 , 43 , 44 , 45 Interestingly, recent studies have demonstrated a distinct role of NEAT1 isoforms in specific tumours. Although NEAT1_1 isoform has been proposed as non‐functional, and NEAT1 functions are mainly considered as NEAT1_2 and paraspeckles‐dependent, 46 NEAT1_1 isoform was documented to be exported to the cytoplasm of breast cancer cells in a glucose‐dependent manner and to promote glycolysis towards cancer cell proliferation, invasion and metastasis. 47 Moreover, NEAT1_1 was reported to facilitate cell growth and the spread of CRC cells compared to the tumour suppressor properties of NEAT1_2, 48 emphasizing the importance of isoform‐specific analysis and clinical validation.

In haematological malignancies, both tumour suppressor 49 , 50 , 51 , 52 and tumour promoting 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 properties of NEAT1 have been reported. Focusing on its oncogenic and pro‐survival advances, NEAT1 overexpression in multiple myeloma (MM) favours plasma cell survival by a positive regulatory loop with DNA damage repair proteins, while NEAT1 silencing inhibits proliferation and triggers apoptosis and chemosensitivity of MM cells in vitro and in vivo. 53 , 54 , 55 Interestingly, MM cell‐derived exosomal NEAT1 was documented recently to inhibit natural killer (NK) cell activity through EZH2‐mediated PXB1 silencing towards immune escape. 56 Moreover, elevated NEAT1 expression has been reported in childhood ALL compared to normal controls, 57 as well as in adult T‐ALL, promoting T‐cell proliferation by sponging miR‐146b‐5p and upregulating NOTCH1. 58 Moreover, NEAT1 is overexpressed in diffuse large B‐cell lymphoma (DLBCL) promoting B‐cell proliferation and lymphomagenesis via the NEAT1/miR‐34b‐5p/GLI1 pathway, 59 and associated with poor patients' survival. 60

Beyond its prognostic relevance, our study offers new biological insights by linking NEAT1_1 isoform overexpression with MRD positivity at the EoI and worse treatment outcome of the patients, suggesting a potential role in early treatment resistance and disease relapse. Although NEAT1_1 has been reported to modulate chemoresistance and survival signalling in other malignancies via ceRNA networks and chromatin remodelling pathways, 42 , 53 , 54 its specific functional role in childhood B‐ALL remains unexplored. Our findings support that NEAT1_1 may exert paraspeckle‐independent ceRNA regulatory functions also in chB‐ALL, as demonstrated in other malignancies, 47 , 48 and future studies involving in vitro NEAT1_1 silencing in primary B‐ALL cells could elucidate its role in treatment evasion and interaction with BFM‐based chemotherapy agents.

In conclusion, our study investigated, for the first time, NEAT1 lncRNA clinical value in chB‐ALL prognostication and treatment outcome. Our analysis highlighted that NEAT1 overexpression in BM blasts at diagnosis is associated with significantly higher risk for relapse and worse post‐treatment survival, independently of clinicopathological data and the clinically used prognostic markers. Most importantly, NEAT1‐fitted multivariate models improved risk stratification and benefited childhood B‐ALL prognostication based on the established and clinically used markers (control model). Overall, evaluation of NEAT1 lncRNA levels at childhood B‐ALL diagnosis results in superior prediction of treatment outcome, paving the way for personalized prognosis as well as tailored therapeutics and monitoring decisions towards modern management of childhood B‐ALL.

AUTHOR CONTRIBUTIONS

Conceptualization : MA and DG. Methodology : MX, AM and MA. Formal analysis : MX and MA. Investigation : MX. Validation : AM, SP and MA. Resources : DD, MN, EM, AES, MB, LK, SP, ASo, MT and ASc. Data curation : MX, AM and MA. Writing—original draft : MA and MX. Writing—review and editing : AM, DD, LK, SP, ASo, MT, ASc and DG. Visualization : MX and MA. Supervision : MA and DG. Project administration : MA. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

The study was approved by the ethics committee of ‘P. & A. Kyriakou’ Children's Hospital, Athens, Greece, and was conducted according to ethical standards of the 1975 Declaration of Helsinki, as revised in 2008.

CONSENT TO PARTICIPATE

Informed consent was obtained from all parents or legal guardians of the children, prior to participation in the study.

Supporting information

Data S1.

ACKNOWLEDGEMENTS

The publication of the article in OA mode was financially supported by HEAL‐Link.

Xagorari M, Marmarinos A, Doganis D, Nikita M, Magkou E, Sfetsiori A‐E, et al. NEAT1 lncRNA overexpression results in short‐term progression and poor treatment outcome in childhood B‐ALL . Br J Haematol. 2025;207(6):2475–2485. 10.1111/bjh.70127

DATA AVAILABILITY STATEMENT

All the data are available from the corresponding author on reasonable request.

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Associated Data

Supplementary Materials

Data S1.

Data Availability Statement

All the data are available from the corresponding author on reasonable request.