RARE DISEASE
Precursor T-cell acute lymphoblastic leukemia
Precursor T-cell acute lymphoblastic leukemia
Precursor T-cell acute lymphoblastic leukemia
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Synonyms: Precursor T-cell acute lymphoblastic leukemia/lymphoma, Precursor T-cell acute lymphocytic leukemia, Precursor T-cell acute lymphocytic leukemia/lymphoma, T-ALL
Drug discovery
0
drugs
With orphan designations
Overview
Precursor T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T-cell precursors, characterized by bone marrow/blood involvement, mediastinal masses, and extramedullary disease. Diagnosis requires >25% bone marrow blasts and T-lineage markers (cCD3+, CD7+). Prognosis varies by age and genetic risk, with relapse rates of 15-30% despite intensive therapy [1][4][6][14].
Burden
Survival: 85% 5-year EFS in pediatric vs. 40-60% in adult patients; ETP-ALL has <40% 5-year OS in adults [4][6][17].
Relapse: 28-30% relapse risk despite nelarabine integration; median survival post-relapse is <1 year [4][5].
Toxicity: 70-80% experience severe infections or cytopenias during induction/consolidation [8][17].
Therapies
Chemotherapy: Dexamethasone-based induction with nelarabine (for CNS prophylaxis) augmented by asparaginase and anthracyclines [5][17].
Targeted agents: Bortezomib (NOTCH1 inhibition), ruxolitinib (JAK/STAT in ETP-ALL), venetoclax (BCL-2 inhibition), and CD38-directed therapies [3][4][13].
Transplant: Allo-HSCT recommended for high-risk/relapsed disease or persistent MRD [4][17].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
2,923 drug discovery papers related to Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2,923 drug discovery papers related to Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class and 0 next-in-class early-stage therapies forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-10 | LDB1-dependent enhancer connectivity defines T-cell leukemia identities and masks metabolic vulnerabilities.
Spatial enhancer connectivity is fundamental to proper gene regulation. Enhancer dysregulation has emerged as a hallmark of cancers, including T-cell acute lymphoblastic leukemias (T-ALL). T-ALL are aggressive malignancies characterized by marked transcriptional heterogeneity driven by distinct stages of developmental arrest and diverse noncoding alterations. How these cancers co-opt nuclear architecture to rewire enhancer connectivity remains poorly understood. Here, we report that the LDB1 chromatin architectural complex is an essential mediator of enhancer-oncogene looping that sustains oncogenic transcriptional programs across multiple T-ALL subtypes. Integrating bulk and single-cell transcriptomic data from patients with T-ALL and healthy hematopoietic controls, we show that the LDB1-dependent regulatory circuitry defines the molecular identities of distinct T-ALL subtypes while restricting plasticity toward alternative cell states. LDB1 loss dismantles chromatin looping among cell state-defining enhancers liberating them to form promiscuous interactions with nearby genes. This enhancer rewiring stimulates expression of key metabolic genes, creating a mevalonate pathway dependency exploitable with statin treatment. Our study establishes LDB1 as a central executor of T-ALL regulatory circuitry and more broadly illustrates chromatin rewiring as a source of targetable dependencies in cancer.
2026-07-10 | Dysregulation of the inside-out signaling pathway in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia.
A major obstacle to improving treatment efficacy and long-term survival in children with T-cell acute lymphoblastic leukemia (T-ALL) is the limited understanding of how leukemia cells infiltrate the central nervous system (CNS). By migrating to the CNS, leukemia cells can evade systemic therapy, contributing to disease progression and relapse. A better understanding of the mechanisms driving CNS infiltration in T-ALL could improve both diagnostic strategies and therapeutic interventions, thereby reducing the risk of CNS-originated relapse. One potential mechanism involves T-cell receptor (TCR)-mediated inside-out signaling, a pathway that regulates migration in normal T-cells and may be hijacked by leukemia cells invading the CNS. To investigate this possibility, we examined the role of this pathway in CNS-infiltrated pediatric T-ALL. RNA-sequencing analysis revealed enrichment of genes associated with the TCR signaling pathway, including adaptor protein SKAP1, a key component of inside-out signaling, in CNS-infiltrated and CNS-relapsed pediatric T-ALL samples. In addition, T-ALL cells exposed to methotrexate and co-cultured with meningeal cells exhibited alterations in signaling events downstream of the TCR. Knockdown of SKAP1 further resulted in reduced viability and proliferation of T-ALL cells. Collectively, these findings suggest that disruption of inside-out signaling may be characteristic for patients with CNS disease and could aid in providing new insights into the transcriptional programs underlying CNS infiltration in pediatric T-ALL.
2026-07-07 | [Novel CD6-targeted CAR-T cell therapy for T-cell acute lymphoblastic leukemia: a safe and efficient strategy to prevent fratricide through gene editing].
Objective: To explore a novel strategy that addresses the dual challenges of fratricide and on-target off-tumor toxicity in current chimeric antigen receptor T-cell (CAR-T) therapy for T-cell acute lymphoblastic leukemia (T-ALL) and to develop a safe and efficacious anti-T-ALL CAR-T product by identifying a new target and compatible gene-editing approach. Methods: Public single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze bone marrow cells extracted from patients with T-ALL and healthy donors, evaluating the differential expression profiles of CD6 and CD7. In investigating the endogenous role of CD6 in CAR-T cells, the CRISPR/Cas9 RNP system was first employed in a CD19 CAR-T model to evaluate the impact of CD6 knockout on the phenotype and activation status of CAR-T cells. Subsequently, CD6-knockout, CD6-targeted CAR-T cells (6KO-6CAR) were constructed, and their functional activities were evaluated. Results: scRNA-seq analysis revealed that CD6 is broadly expressed in T-ALL. Compared with the traditional target CD7, which is also expressed in a subset of normal hematopoietic stem/progenitor cells and myeloid cells, CD6 exhibits a more restricted expression profile, exhibiting superior safety characteristics. Studies on the CD19 CAR-T model indicated that CD6 knockout enables CAR-T cells to maintain a superior functional state: their baseline activation level (CD25 expression) was reduced (P<0.05) while generating a higher proportion of TNF-α(+)IFN-γ(+) cells (P<0.05) upon antigen stimulation. The further constructed 6KO-6CAR cells exhibited potent specific activation (significantly upregulated CD107a expression level, all P<0.001) and cytotoxicity (all P<0.05) against multiple CD6(+) T-ALL cell lines (MOLT-4, CCRF-CEM, and Jurkat) in vitro. Conclusion: CD6 is a novel therapeutic target for T-ALL with high coverage and a favorable safety profile, and knocking out endogenous CD6 globally optimizes the intrinsic functional state of CAR-T cells. Constructing 6KO-6CAR based on the CRISPR/Cas9 technology addresses fratricide in CAR-T cells while enhancing their antitumor functionality, thereby providing a novel immunotherapy regimen with safety and clinical translational potential for relapsed/refractory T-ALL.
2026-07-10 | LDB1-dependent enhancer connectivity defines T-cell leukemia identities and masks metabolic vulnerabilities.
Spatial enhancer connectivity is fundamental to proper gene regulation. Enhancer dysregulation has emerged as a hallmark of cancers, including T-cell acute lymphoblastic leukemias (T-ALL). T-ALL are aggressive malignancies characterized by marked transcriptional heterogeneity driven by distinct stages of developmental arrest and diverse noncoding alterations. How these cancers co-opt nuclear architecture to rewire enhancer connectivity remains poorly understood. Here, we report that the LDB1 chromatin architectural complex is an essential mediator of enhancer-oncogene looping that sustains oncogenic transcriptional programs across multiple T-ALL subtypes. Integrating bulk and single-cell transcriptomic data from patients with T-ALL and healthy hematopoietic controls, we show that the LDB1-dependent regulatory circuitry defines the molecular identities of distinct T-ALL subtypes while restricting plasticity toward alternative cell states. LDB1 loss dismantles chromatin looping among cell state-defining enhancers liberating them to form promiscuous interactions with nearby genes. This enhancer rewiring stimulates expression of key metabolic genes, creating a mevalonate pathway dependency exploitable with statin treatment. Our study establishes LDB1 as a central executor of T-ALL regulatory circuitry and more broadly illustrates chromatin rewiring as a source of targetable dependencies in cancer.
2026-07-10 | Dysregulation of the inside-out signaling pathway in CNS-infiltrated pediatric T-cell acute lymphoblastic leukemia.
A major obstacle to improving treatment efficacy and long-term survival in children with T-cell acute lymphoblastic leukemia (T-ALL) is the limited understanding of how leukemia cells infiltrate the central nervous system (CNS). By migrating to the CNS, leukemia cells can evade systemic therapy, contributing to disease progression and relapse. A better understanding of the mechanisms driving CNS infiltration in T-ALL could improve both diagnostic strategies and therapeutic interventions, thereby reducing the risk of CNS-originated relapse. One potential mechanism involves T-cell receptor (TCR)-mediated inside-out signaling, a pathway that regulates migration in normal T-cells and may be hijacked by leukemia cells invading the CNS. To investigate this possibility, we examined the role of this pathway in CNS-infiltrated pediatric T-ALL. RNA-sequencing analysis revealed enrichment of genes associated with the TCR signaling pathway, including adaptor protein SKAP1, a key component of inside-out signaling, in CNS-infiltrated and CNS-relapsed pediatric T-ALL samples. In addition, T-ALL cells exposed to methotrexate and co-cultured with meningeal cells exhibited alterations in signaling events downstream of the TCR. Knockdown of SKAP1 further resulted in reduced viability and proliferation of T-ALL cells. Collectively, these findings suggest that disruption of inside-out signaling may be characteristic for patients with CNS disease and could aid in providing new insights into the transcriptional programs underlying CNS infiltration in pediatric T-ALL.
2026-07-07 | [Novel CD6-targeted CAR-T cell therapy for T-cell acute lymphoblastic leukemia: a safe and efficient strategy to prevent fratricide through gene editing].
Objective: To explore a novel strategy that addresses the dual challenges of fratricide and on-target off-tumor toxicity in current chimeric antigen receptor T-cell (CAR-T) therapy for T-cell acute lymphoblastic leukemia (T-ALL) and to develop a safe and efficacious anti-T-ALL CAR-T product by identifying a new target and compatible gene-editing approach. Methods: Public single-cell RNA sequencing (scRNA-seq) datasets were utilized to analyze bone marrow cells extracted from patients with T-ALL and healthy donors, evaluating the differential expression profiles of CD6 and CD7. In investigating the endogenous role of CD6 in CAR-T cells, the CRISPR/Cas9 RNP system was first employed in a CD19 CAR-T model to evaluate the impact of CD6 knockout on the phenotype and activation status of CAR-T cells. Subsequently, CD6-knockout, CD6-targeted CAR-T cells (6KO-6CAR) were constructed, and their functional activities were evaluated. Results: scRNA-seq analysis revealed that CD6 is broadly expressed in T-ALL. Compared with the traditional target CD7, which is also expressed in a subset of normal hematopoietic stem/progenitor cells and myeloid cells, CD6 exhibits a more restricted expression profile, exhibiting superior safety characteristics. Studies on the CD19 CAR-T model indicated that CD6 knockout enables CAR-T cells to maintain a superior functional state: their baseline activation level (CD25 expression) was reduced (P<0.05) while generating a higher proportion of TNF-α(+)IFN-γ(+) cells (P<0.05) upon antigen stimulation. The further constructed 6KO-6CAR cells exhibited potent specific activation (significantly upregulated CD107a expression level, all P<0.001) and cytotoxicity (all P<0.05) against multiple CD6(+) T-ALL cell lines (MOLT-4, CCRF-CEM, and Jurkat) in vitro. Conclusion: CD6 is a novel therapeutic target for T-ALL with high coverage and a favorable safety profile, and knocking out endogenous CD6 globally optimizes the intrinsic functional state of CAR-T cells. Constructing 6KO-6CAR based on the CRISPR/Cas9 technology addresses fratricide in CAR-T cells while enhancing their antitumor functionality, thereby providing a novel immunotherapy regimen with safety and clinical translational potential for relapsed/refractory T-ALL.
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