T-cell Acute Lymphoblastic Leukemia Research Articles

A multiomic atlas identifies a treatment-resistant, bone marrow progenitor-like cell population in T cell acute lymphoblastic leukemia.

Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to curing T cell acute lymphoblastic leukemia (T-ALL). While tumor heterogeneity has been implicated in treatment failure, the cellular and genetic factors contributing to resistance and relapse remain unknown. Here we linked tumor subpopulations with clinical outcome, created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic analysis to a diverse cohort of 40 T-ALL cases. We identified a bone marrow progenitor (BMP)-like leukemia subpopulation associated with treatment failure and poor overall survival. The single-cell-derived molecular signature of BMP-like blasts predicted poor outcome across multiple subtypes of T-ALL and revealed that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. Through in silico and in vitro drug screenings, we identified a therapeutic vulnerability of BMP-like blasts to apoptosis-inducing agents including venetoclax. Collectively, our study establishes multiomic signatures for rapid risk stratification and targeted treatment of high-risk T-ALL.

High CD44 expression and enhanced E-selectin binding identified as biomarkers of chemoresistant leukemic cells in human T-ALL.

T-cell acute lymphoblastic leukemia (T-ALL) is a hematopoietic malignancy characterized by increased proliferation and incomplete maturation of T-cell progenitors, for which relapse is often of poor prognosis. To improve patient outcomes, it is critical to understand the chemoresistance mechanisms arising from cell plasticity induced by the bone marrow (BM) microenvironment. Single-cell RNA sequencing of human T-ALL cells from adipocyte-rich and adipocyte-poor BM revealed a distinct leukemic cell population defined by quiescence and high CD44 expression (Ki67neg/lowCD44high). During in vivo treatment, these cells evaded chemotherapy, and were further called Chemotherapy-resistant Leukemic Cells (CLCs). Patient sample analysis revealed Ki67neg/lowCD44high CLCs at diagnosis and during relapse, with each displaying a specific transcriptomic signature. Interestingly, CD44high expression in T-ALL Ki67neg/low CLCs was associated with E-selectin binding. Analysis of 39 human T-ALL samples revealed significantly enhanced E-selectin binding activity in relapse/refractory samples compared with drug-sensitive samples. These characteristics of chemoresistant T-ALL CLCs provide key insights for prognostic stratification and novel therapeutic options.

Nelarabine-combined chemotherapy improves outcome of T-cell acute lymphoblastic leukemia but shows more severe neurotoxicity: JALSG T-ALL213-O.

We investigated the effectiveness and safety of nelarabine (NEL)-combined chemotherapy for newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients. We conducted a phase II trial, T-ALL213-O, where adult T-ALL patients aged 25 to 64 were treated by a regimen based on that used in our previous study, ALL202-O. The main modifications from ALL202-O to T-ALL213-O were as follows: (1) NEL-combined chemotherapy, instead of consolidation (C)1, was used for non-complete remission (CR) patients after induction therapy (IND)1 as IND2; (2) NEL treatments were inserted into C3 and C5 on day 29. Twenty-four patients were analyzed. Ten patients did not receive NEL treatment due to therapy termination prior to C3. Three-year event-free survival (EFS) was 70%, with 52% as the lower limit of its 90% confidence interval, which exceeded the threshold of 25%; thus, the study treatment was considered effective. The CR rates by IND1, IND2, and both were 75%, 100%, and 88%, respectively. The 5-year EFS and 5-year overall survival rates were 66% and 70%, respectively, with median follow-ups of 7.7 and 7.8 years. The addition of NEL improved the CR rate but not survival, compared with T-ALL patients in ALL202-O. Severe neuropathy after NEL administration was observed at a high frequency. Seven (50%) of 14 patients treated with NEL showed grade 3 peripheral neuropathy and/or gait disturbance. The neurotoxicity was considered stronger than that previously reported. Combination therapy of NEL at this dose and intensive multidrug chemotherapy is associated with a high risk of severe neurotoxicity (JALSG T-ALL213-O, UMIN000010642).

A rare case of pediatric T-cell acute lymphoblastic leukemia with myeloid mimicry

Acute lymphoblastic leukemia (ALL) with granular blasts was historically referred to as “granular ALL”, but this is not recognized as a distinct entity in the current WHO classification. This rare morphological feature is predominantly associated with a B-cell immunophenotype, while T-ALL with prominent cytoplasmic granules is extremely rare, with limited available genetic, molecular, and prognostic data. Here, we report a unique case of ALL in a 9-year-old girl. Initial blood tests revealed leukocytosis, and both peripheral blood and bone marrow morphology showed a high number of blasts with granular cytoplasm and bilobed nuclei. Immunophenotyping confirmed T-cell origin. The patient tested positive for KMT2A::AFDN, with WT1 overexpression, and NRAS and EZH2 mutations were detected by next-generation sequencing (NGS). Remarkably, the patient achieved complete remission after treatment and has shown no signs of relapse for nearly four years. Her favorable response to conventional therapy underscores the importance of molecular phenotyping in the treatment of this disease. The continued use of NGS to gather relevant molecular data is crucial for further understanding the molecular phenotype and prognosis of such atypical ALL cases.

A meta-analysis of the prognostic significance of CDKN deletions in acute lymphoblastic leukaemia

Background B-cell acute lymphoblastic leukaemia (B-ALL) and T-cell acute lymphoblastic leukaemia (T-ALL) are both types of acute lymphoblastic leukaemia (ALL), which is a cancer of the blood and bone marrow characterized by the rapid proliferation of immature lymphocytes. In ALL, CDKN gene deletions have been extensively studied regarding their prognostic significance. The purpose of this meta-analysis is to determine whether there is a consistent relationship between CDKN gene variations and the incidence of lymphocytic leukaemia. Materials and methods The following databases contain relevant studies published between inception and 25 October 2023: PubMed, EMBASE, the Cochrane library and Web of Science were comprehensively searched. Based on the random-effects or fixed-effects model, the hazard ratio (HR) and its 95% confidence interval (95% CI) were pooled. A subgroup analysis and sensitivity analysis were also conducted. We estimated publication bias using a funnel plot. Results This meta-analysis included 19 studies containing 1333 patients. Among included studies, 12 studies only reported B-ALL, four studies included patients with T-ALL and B-ALL, and three studies reported T-ALL. A deletion of the CDKN gene was found to be an adverse indicator of both EFS (HR = 1.83, 95% CI: 1.03–2.62), DFS (HR = 1.49, 95% CI 1.23–1.77), RFS (HR = 1.34, 95% CI 0.96–1.73) and OS (HR = 1.39, 95% CI 1.19–1.58). Single-arm emphasized the greater influence on OS. The subgroup analysis based on the CDKN2A, CDKN2A/b and different ALL subtypes further strengthen the validity of the findings. Conclusions Our meta-analysis revealed that CDKN gene deletions (including CDKN 2A/B, CDKN 2A) serve as adverse prognostic indicators for T-ALL/B-ALL patients.

The apoptotic and anti-proliferative effects of Neosetophomone B in T-cell acute lymphoblastic leukaemia via PI3K/AKT/mTOR pathway inhibition.

The phosphatidylinositol 3-kinase/Protein Kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signalling pathway is pivotal in various cancers, including T-cell acute lymphoblastic leukaemia (T-ALL), a particularly aggressive type of leukaemia. This study investigates the effects of Neosetophomone B (NSP-B), a meroterpenoid fungal metabolite, on T-ALL cell lines, focusing on its anti-cancer mechanisms and therapeutic potential. NSP-B significantly inhibited the proliferation of T-ALL cells by inducing G0/G1 cell cycle arrest and promoting caspase-dependent apoptosis. Additionally, NSP-B led to the dephosphorylation and subsequent inactivation of the PI3K/AKT/mTOR signalling pathway, a critical pathway in cell survival and growth. Molecular docking studies revealed a strong binding affinity of NSP-B to the active site of AKT, primarily involving key residues crucial for its activity. Interestingly, NSP-B treatment also induced apoptosis and significantly reduced proliferation in phytohemagglutinin-activated primary human CD3+ T cells, accompanied by a G0/G1 cell cycle arrest. Importantly, NSP-B did not affect normal primary T cells, indicating a degree of selectivity in its action, targeting only T-ALL cells and activated T cells. In conclusion, our findings highlight the potential of NSP-B as a novel therapeutic agent for T-ALL, specifically targeting the aberrantly activated PI3K/AKT/mTOR pathway and being selective in action. These results provide a strong basis for further investigation into NSP-B's anti-cancer properties and potential application in T-ALL clinical therapies.

Delineating Notch1 and Notch2: Receptor-Specific Significance and Therapeutic Importance of Pinpoint Targeting Strategies for Hematological Malignancies.

Notch1 and Notch2, transmembrane receptors belonging to the Notch family, are pivotal mediators of intercellular communication and have profound implications including cell fate determination, embryonic development, and tissue homeostasis in various cellular processes. Despite their structural homology, Notch1 and Notch2 exhibit discrete phenotypic characteristics and functional nuances that necessitate their individualized targeting in specific medical scenarios. Aberrant Notch signaling, often driven by the dysregulated activity of one receptor over the other, is implicated under various pathological conditions. Notch1 dysregulation is frequently associated with T-cell acute lymphoblastic leukemia, whereas Notch2 perturbations are linked to B-cell malignancies and solid tumors, including breast cancer. Hence, tailored therapeutic interventions that selectively inhibit the relevant Notch receptor need to be devised to disrupt the signaling pathways driving the specific disease phenotype. In this review, we emphasize the importance of distinct tissue-specific expression patterns, functional divergence, disease-specific considerations, and the necessity to minimize off-target effects that collectively underscore the significance of "individualized" targeting for Notch1 and Notch2. This comprehensive review sheds light on the receptor-specific characteristics of Notch1 and Notch2, providing insights into their roles in cellular processes and offering opportunities for developing tailored therapeutic interventions in the fields of biomedical research and clinical practice.

NCMP-29. BRAIN LESIONS IN A TEEN WITH NEWLY DIAGNOSED T-CELL ALL AND SARS-COV-2 INFECTION

Abstract T-cell Lymphoblastic Leukemia (T-cell ALL) accounts for up to 15% of all newly diagnosed cases of acute lymphoblastic leukemia in pediatric patients (0-18 years old). Patients are at risk of opportunistic infections during induction therapy with up to 2% developing blood stream infections when their absolute neutrophil count is above 1,500. We report a case of a 15-year-old female with High-Risk T-cell ALL, CNS1 (negative CNS disease), presenting with three days of headaches, photophobia, and non-neutropenic fever. She completed induction chemotherapy one week earlier with vincristine, daunorubicin, calaspargase and a 28-day course of dexamethasone. On physical exam, she had no focal deficits or changes in sensation or strength. CBC was notable for a white blood cell count: 7500, hemoglobin: 8.6, platelets: 328,000 and ANC (Absolute Neutrophil Count): 4700. The patient was also COVID positive on admission. A contrast enhanced MRI brain demonstrated multiple diffusion restricting and peripherally enhancing lesions, concerning for intracranial abscesses. Neurosurgery performed a burr hole craniotomy and aspirated 5 mL of purulent drainage, the culture of which grew Aspergillus fumigatus complex. The patient was started empirically on Voriconazole, in addition to broad spectrum antibiotic coverage pending culture results, due to excellent CNS penetration and proven superiority to amphotericin-based therapy for invasive aspergillosis. Micafungin was added due to CT chest demonstrating nodular infiltrates, suggesting primary pulmonary aspergillosis with CNS dissemination. The patient improved symptomatically without further sequelae. Patients with COVID-19 on prolonged courses of corticosteroids are at higher risk of developing fungal co-infections regardless of neutrophil count. While pulmonary aspergillosis is the most common location of a COVID-19 aspergillus coinfection, there have been documented reports of intracranial micro-abscesses. Contrast-enhanced brain MRI should be obtained in any patient with a recent history of COVID-19 presenting with new neurological symptoms, especially in a patient with a recent history of corticosteroids.

Exploring the Biological Activity of a Humanized Anti-CD99 ScFv and Antibody for Targeting T Cell Malignancies.

CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in "ScFvkh" design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10-10 M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.

Mutations at BCL11B Exon 4 Associated with T Cell Acute Lymphoblastic Leukemia Are Facilitated by AID and Formation of Non-B DNA Conformations.

One of the primary reasons behind the pathogenesis of T cell acute lymphoblastic leukemia (T-ALL) is the deregulation of the transcription factor BCL11B. The exon 4 of BCL11B harbors several driver mutations, which abolishes its DNA-binding ability. The high frequency of C > T or G > A conversion in close vicinity of AID (Activation-induced cytidine deaminase)-hotspot motifs in the deregulated gene prompted us to investigate the role of AID in BCL11B mutagenesis. Our results reveal that AID is expressed in T-ALL patient-derived cells, binds to BCL11B fragile region (FR) in exon 4 of T cells invivo, and generates a signature mutation pattern in this region. The mutation frequency in BCL11B FR could be modulated upon overexpression of the AID gene in the knockout background, further suggesting the involvement of AID in BCL11B mutagenesis. Importantly, various lines of experimentation reveal that BCL11B FR could fold into parallel G-quadruplex, triplex, and hairpin structures, which could act as a replication/transcription block, causing mutagenesis. Thus, our results suggest that AID binds to BCL11B exon 4 due to non-B DNA formation, causing U:G mismatches or replication blocks, which, when repaired erroneously, generates deleterious mutations, resulting in loss of functionality of BCL11B, and thus becomes the cause of T-ALL.

The third generation AKR1C3-activated prodrug, ACHM-025, eradicates disease in preclinical models of aggressive T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that expresses high levels of the enzyme aldo-keto reductase family 1 member C3 (AKR1C3). To exploit this finding, we developed a novel prodrug, ACHM-025, which is selectively activated by AKR1C3 to a nitrogen mustard DNA alkylating agent. We show that ACHM-025 has potent in vivo efficacy against T-ALL patient-derived xenografts (PDXs) and eradicated the disease in 7 PDXs. ACHM-025 was significantly more effective than cyclophosphamide both as a single agent and when used in combination with cytarabine/6-mercaptopurine. Notably, ACHM-025 in combination with nelarabine was curative when used to treat a chemoresistant T-ALL PDX in vivo. The in vivo efficacy of ACHM-025 directly correlated with AKR1C3 expression levels, providing a predictive biomarker for response. Together, our work provides strong preclinical evidence highlighting the potential of ACHM-025 as a targeted and effective therapy for aggressive forms of T-ALL.

Transcriptional regulatory program controlled by MYB in T-cell acute lymphoblastic leukemia.

The transcription factor MYB is frequently upregulated in T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy originating from T-cell precursors. Here, we demonstrate that MYB plays a crucial role by regulating genes essential for T-ALL pathogenesis. Integrative analysis reveals a long MYB isoform, ENST00000367814.8, which is dominantly expressed and confers a proliferative advantage in T-ALL cells. Rapid depletion of MYB via dTAG-mediated protein degradation affects a large number of genes, which can be classified into early response or late response genes based on their kinetics. Early response genes include many genes involved in hematopoiesis, such as TAL1, RUNX1, GATA3, IKZF2, and CXCR4. Their expression can be recovered at later time-points, suggesting the presence of a negative feedback loop mechanism. In contrast, late response genes, which are continuously downregulated after MYB depletion, includes many genes involved in cell proliferation as well as TAL1 targets, thereby affecting the cellular phenotype.

Combining array-assisted SERS microfluidic chips and machine learning algorithms for clinical leukemia phenotyping

The disease progression and treatment options of leukemia between different subtypes vary considerably, emphasizing the importance of phenotyping. However, early typing of leukemia remains challenging due to the lack of highly sensitive and specific analytical tools. Herein, we propose a SERS-based platform for the classification of acute lymphoblastic T-cell leukemia (T-ALL) and chronic myeloid leukemia (CML) through the combination of machine learning and microfluidic chips. The ordered arrays in microfluidic channels reshape the microscopic flow field and contacting interfaces, facilitating the uniform and efficient capture of tumor cells. To enable phenotypic analysis, spectrally orthogonal SERS aptamer nanoprobes were applied, providing composite spectral signatures of individual cells in accordance with surface protein expression. Further, machine learning algorithms were employed to analyze the SERS signatures automatically, resulting in an accuracy of 98.6 % for 73 clinical blood samples. The results demonstrate that this platform holds promising potential for clinical leukemia diagnosis and precision medicine.

The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of pediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the tricarboxylic acid cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

Aptamer sgc8-Modified PAMAM Nanoparticles for Targeted siRNA Delivery to Inhibit BCL11B in T-Cell Acute Lymphoblastic Leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disease with limited targeted therapy options. Overexpression of B-cell lymphoma/leukemia 11B is frequently observed in T-ALL and contributes to leukemogenesis. Knockdown of BCL11B inhibits T-ALL cell proliferation and induces apoptosis, making it a potential therapeutic target. However, the clinical application of siRNA therapies is hindered by challenges such as poor delivery efficiency and limited clinical outcomes. We developed a targeted delivery system for BCL11B siRNA (siBCL11B) using generation 5 polyamidoamine (G5-PAMAM) dendrimers conjugated with the sgc8 aptamer, which specifically binds to the T-ALL cell membrane protein PTK7. This nanoparticle, designated G5-sgc8-siBCL11B, was designed to selectively deliver siRNA to T-ALL cells. In vitro and in vivo experiments were conducted to evaluate its therapeutic efficacy and safety. We demonstrate that sgc8-conjugated siBCL11B nanoparticles selectively and efficiently target BCL11B-overexpressing T-ALL cells, significantly inhibiting cell viability and promoting apoptosis while exhibiting minimal impact on the viability of normal T cells. In T-ALL mouse model studies, G5-sgc8-siBCL11B and G5-siBCL11B significantly inhibited the progression of T-ALL in vivo, extending the survival of mice compared to the control (CTR), G5, and G5-sgc8 groups. Although there was no significant difference in survival between the G5-sgc8-siBCL11B and G5-siBCL11B groups, a trend towards improved survival was observed (p = 0.0993). The G5-sgc8-siBCL11B nanoparticle system demonstrated efficient delivery and significant therapeutic efficacy, highlighting its potential as a promising novel approach for the treatment of T-ALL.

Pathway of LCK Tyrosine Kinase and mTOR Signaling in Children with T-Cell Acute Lymphoblastic Leukemia.

The aim of this study is to analyze available research on targeting signaling pathways for the development of new drugs in patients with T-cell acute lymphoblastic leukemia (T-ALL). This analysis focuses specifically on the role of LCK tyrosine kinase and mTOR signaling pathways in pediatric patients. Outcome: Current literature suggests that these pathways play a significant role in the regulation of T-cell cycles, making them potential therapeutic targets. However, despite promising findings, there remains a need for further research, particularly in pediatric populations, to fully understand the therapeutic implications and to optimize drug development. The conclusion drawn from this analysis highlights the significant influence of LCK and mTOR on T-cell cycle regulation, underscoring the importance of continued investigation in this area.

Results of the prospective EORTC Children Leukemia Group study 58081 in precursor B- and T-cell acute lymphoblastic leukemia.

Here, we report the results of the prospective cohort study EORTC-CLG 58081 and compare them to the control arm of the randomized phase 3 trial EORTC-CLG 58951, on which treatment recommendations were built. In both studies, patients aged 1-18 years with BCR::ABL1 negative acute lymphoblastic leukemia of the B-lineage (B-ALL) or T-lineage (T-ALL) were treated using a BFM backbone without cranial irradiation. Similarly to the control arm of 58951, prednisolone (PRED) 60 mg/m2/day was used for induction therapy, but a few modifications were made. Dexamethasone (DXM) was used in average-risk 2 (AR2) T-ALL and B-ALL during induction, 10 and 6 mg/m2/day, respectively. Leucovorin rescue was delayed to 42 h instead of 36 h after initiation of high-dose methotrexate, and a postconsolidation MRD time point was added to stratify patients. Between 2011 and 2017, 835 patients were prospectively enrolled in the 58081 study. Overall, the 5-year event-free survival (EFS) was 84.8% versus 83.6% (hazard ratio [HR], 0.96 [95% confidence interval [CI]: 0.76-1.21]) for 58081 versus 58951 considered as a control group, respectively, 84.3% versus 84.9% (HR, 1.06 [99% CI: 0.75-1.49]) in B-ALL but 87.3% versus 76.6% (HR, 0.59 [99% CI: 0.28-1.24]) in T-ALL. The comparison between the two studies regarding EFS differed by risk group (p = 0.012). The HR was 2.15 (99% CI: 0.67-6.85) for very low-risk but 0.34 (99% CI: 0.13-0.89) for AR2. The particularly favorable results observed in the T-ALLs and AR2 subgroups suggest the benefit of using DXM in specific patient groups and highlight the importance of risk stratification.

Early T-cell precursor acute lymphoblastic leukemia: diagnostic pitfalls, genomic alteration, novel therapeutics, and minimal residual disease monitoring

Early precursor T-cell acute lymphoblastic leukemia (ETP-ALL) is a rare type of T-cell ALL (T-ALL) that was initially described in 2009. Since its initial description, it has been formally recognized as a distinct entity, according to the 2016 World Health Organization classification. ETP-ALL is characterized by unique immunophenotypic and genomic profiles. The diagnosis and management of ETP-ALL remain challenging. Poorer outcomes, high incidence of induction failure and relapsed/refractory disease demand novel therapies. This review emphasizes the challenges of initial diagnosis, the molecular mechanisms underlying leukemogenesis, and the available therapeutic options. Additionally, it discusses the importance of induction failure, the prognostic value of detecting minimal residual disease, and the implications of hematopoietic stem cell transplantation, along with emerging novel therapies.

Super-Enhancer-Driven IRF2BP2 is Activated by Master Transcription Factors and Sustains T-ALL Cell Growth and Survival.

Super enhancers (SEs) are large clusters of transcriptional enhancers driving the expression of genes crucial for defining cell identity. In cancer, tumor-specific SEs activate key oncogenes, leading to tumorigenesis. Identifying SE-driven oncogenes in tumors and understanding their functional mechanisms is of significant importance. In this study, a previously unreported SE region is identified in T-cell acute lymphoblastic leukemia (T-ALL) patient samples and cell lines. This SE activates the expression of interferon regulatory factor 2 binding protein 2 (IRF2BP2) and is regulated by T-ALL master transcription factors (TFs) such as ETS transcription factor ERG (ERG), E74 like ETS transcription factor 1 (ELF1), and ETS proto-oncogene 1, transcription factor (ETS1). Hematopoietic system-specific IRF2BP2 conditional knockout mice is generated and showed that IRF2BP2 has minimal impact on normal T cell development. However, in vitro and in vivo experiments demonstrated that IRF2BP2 is crucial for T-ALL cell growth and survival. Loss of IRF2BP2 affects the MYC and E2F pathways in T-ALL cells. Cleavage under targets and tagmentation (CUT&Tag) assays and immunoprecipitation revealed that IRF2BP2 cooperates with the master TFs of T-ALL cells, targeting the enhancer of the T-ALL susceptibility gene recombination activating 1 (RAG1) and modulating its expression. These findings provide new insights into the regulatory network within T-ALL cells, identifying potential new targets for therapeutic intervention.

Branching NOTCH1 to DNA damage in T-cell acute lymphoblastic leukemia.

Not available.