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
2,944 drug discovery papers about Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,944 drug discovery papers about Precursor T-cell acute lymphoblastic leukemia, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | SETD5 regulates leukemic initiation and infiltration in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by aberrant epigenetic regulation. Although SET domain-containing 5 (SETD5) is structurally classified as a member of the histone methyltransferase family, it lacks canonical methyltransferase activity and functions primarily through nonenzymatic mechanisms. While recognized as a modulator in normal hematopoiesis, the role of SETD5 in T-ALL remains undefined. Here, we show that SETD5 contributes to efficient T-ALL initiation and progression in the models examined. Using ICN1-driven murine T-ALL models (Vav-Cre;Setd5fl/fl and Mx1-Cre;Setd5fl/fl), we show that genetic ablation of Setd5 impairs efficient leukemia initiation. In transplantation assays, Setd5 depletion reduces leukemia burden, prolongs survival, and impairs leukemic infiltration into the spleen, liver, and thymus. Mechanistically, transcriptomic profiling of Setd5-deficient CD3+ T-ALL cells reveals selective repression of transcriptional programs governing cell migration, motility, and cytoskeletal organization. Key regulators of actin cytoskeleton remodeling and extracellular matrix interaction-including Plxnb2, Mmp14, Ceacam1, and Clstn1-are among the most downregulated genes, as validated by RT-qPCR. Furthermore, SETD5 knockdown in the human T-ALL cell lines Jurkat and MOLT-4 results in a marked reduction in proliferation and migration. Our findings demonstrate that SETD5 contributes to T-ALL progression by regulating transcriptional programs that contribute to leukemic cell migration and infiltration, suggesting that SETD5-associated transcriptional programs warrant further investigation as potential vulnerabilities in T-ALL.
2026-08-07 | Treatment outcome in pediatric patients with T-ALL in Brazil.
Several studies conducted in high-income countries (HICs) have demonstrated that treatment intensification in pediatric T-cell acute lymphoblastic leukemia (T-ALL) improved survival outcomes. However, studies in low- and middle-income countries (LMICs) remain scarce. In this study, we evaluated survival rates and their associations with clinical factors within the context of the Brazilian Unified Health System. Data from 86 patients aged 0-19 years, diagnosed with T-ALL at one of four pediatric oncology reference centers of the Brazilian Unified Health System, were included in the study. Clinical, demographic, and laboratory variables were collected through a retrospective analysis of medical records. Cohort survival rates revealed that the 5-year overall survival probability (pOS) and event-free survival probability (pEFS) for patients with T-ALL were 47% (37.3-59.3) and 43.2% (33.5-55.7), respectively, with infection being the main cause of death (69.4%). In both bivariate and multivariate analyses, the presence of adenomegaly at diagnosis was associated with lower pOS and pEFS. In addition, the GBTLI-HR protocol achieved the highest pOS (70.0%), compared to the 35.0% and 32.0% observed with the ALL IC-BFM 2002-HR and ALL IC-BFM 2009-HR protocols, respectively. This reinforces the need for context-specific adaptations of intensive treatment protocols in LMICs. This study offers valuable insights into the clinical and demographic characteristics of patients with T-ALL from Brazil, highlighting substantially higher mortality rates than those reported in HICs, primarily attributed to high infection rates.
2026-08-07 | Synergistic apoptotic induction in acute lymphoblastic leukemia cells: exploring the role of EAAT1 inhibition by UCPH-101 in combination with asparaginase.
Despite advances in treating acute lymphoblastic leukemia (ALL), resistance to asparaginase (ASNase) remains a major clinical hurdle. Recent evidence suggests that leukemic cells may evade ASNase-induced cytotoxicity by upregulating the glutamate/aspartate transporter EAAT1 (SLC1A3). This study aimed to evaluate whether pharmacological inhibition of EAAT1 using UCPH-101 could enhance the inhibitory effects of ASNase in T-ALL models. Using patient-derived samples and established T-ALL cell lines (MOLT-4 and Jurkat) we assessed the effects of ASNase and UCPH-101, both alone and in combination. Combinations were designed based on IC50-based fixed-ratio dosing, including sub-IC50 and supra-IC50 concentrations. Effects on cell viability, apoptosis, and apoptosis related gene expression were evaluated using standardized in vitro assays. Synergy was evaluated using the combination index (CI) method on the Chou-Talalay model. Synergy analysis based on CI values revealed synergistic interactions (CI < 1) at sub and supra IC50 concentrations of both agents in MOLT-4 and Jurkat cells. Dual targeting of amino acid metabolism through ASNase and EAAT1 inhibition resulted in significantly reduced cell viability and increased apoptotic cell death compared to controls. Combinatorial treatment led to significant alterations in the expression of key apoptotic regulators, suggesting a disruption of metabolic adaptation mechanisms in both leukemic cell lines. These findings demonstrate that EAAT1 inhibition augments ASNase anti-leukemic activity in preclinical ALL models, revealing a metabolic vulnerability that can be exploited therapeutically. The mechanistic insights reported herein support further exploration of EAAT1-targeted strategies to improve outcomes in T-ALL.
2026-08-04 | Supplementary Figure 7 from PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4
<p>Supplementary Figure 7. PAMD-Ch17 induces mitochondrial dysfunction in Molt-4 Cells.</p>
2026-08-04 | Data from PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4
<div>Abstract<p>PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse acute myeloid leukemia cells. To investigate the mechanism of PAMD-Ch17’s novel antileukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-cell acute lymphoblastic leukemia (T-ALL) cell lines being highly sensitive. Surprisingly, <i>CXCR4</i> knockout T-ALL cells were equally sensitive to PAMD-Ch17. Using a fluorescently tagged PAMD-Ch17, we found that the drug colocalized to mitochondria. We also found that PAMD-Ch17 induced changes in the expression of genes related to mitochondrial function, increased levels of mitochondrial superoxide, and decreased mitochondrial membrane potential. Using Seahorse assays, we found that PAMD-Ch17 decreased baseline oxygen consumption, ATP production, and proton leakage. In addition, we identified ATP synthase subunits as binding partners of PAMD-Ch17 and showed that the polymer, but not AMD3100, inhibited ATP synthase activity. In mouse primary T-ALL, but not healthy bone marrow cells, PAMD-Ch17 induced both mitochondrial superoxide and cell death. Using human bone marrow organoids, we found that PAMD-Ch17 induced mitochondrial superoxide and cell death in T-ALL cells from patients, but not in healthy stromal and hematopoietic cells. Collectively, our results indicate that PAMD-Ch17 has antileukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4-independent, mitochondrial-based mechanism. These findings support the further development of PAMDs as potential therapeutics for patients with T-ALL.</p></div>
2026-08-13 | SETD5 regulates leukemic initiation and infiltration in T-cell acute lymphoblastic leukemia.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy characterized by aberrant epigenetic regulation. Although SET domain-containing 5 (SETD5) is structurally classified as a member of the histone methyltransferase family, it lacks canonical methyltransferase activity and functions primarily through nonenzymatic mechanisms. While recognized as a modulator in normal hematopoiesis, the role of SETD5 in T-ALL remains undefined. Here, we show that SETD5 contributes to efficient T-ALL initiation and progression in the models examined. Using ICN1-driven murine T-ALL models (Vav-Cre;Setd5fl/fl and Mx1-Cre;Setd5fl/fl), we show that genetic ablation of Setd5 impairs efficient leukemia initiation. In transplantation assays, Setd5 depletion reduces leukemia burden, prolongs survival, and impairs leukemic infiltration into the spleen, liver, and thymus. Mechanistically, transcriptomic profiling of Setd5-deficient CD3+ T-ALL cells reveals selective repression of transcriptional programs governing cell migration, motility, and cytoskeletal organization. Key regulators of actin cytoskeleton remodeling and extracellular matrix interaction-including Plxnb2, Mmp14, Ceacam1, and Clstn1-are among the most downregulated genes, as validated by RT-qPCR. Furthermore, SETD5 knockdown in the human T-ALL cell lines Jurkat and MOLT-4 results in a marked reduction in proliferation and migration. Our findings demonstrate that SETD5 contributes to T-ALL progression by regulating transcriptional programs that contribute to leukemic cell migration and infiltration, suggesting that SETD5-associated transcriptional programs warrant further investigation as potential vulnerabilities in T-ALL.
2026-08-07 | Treatment outcome in pediatric patients with T-ALL in Brazil.
Several studies conducted in high-income countries (HICs) have demonstrated that treatment intensification in pediatric T-cell acute lymphoblastic leukemia (T-ALL) improved survival outcomes. However, studies in low- and middle-income countries (LMICs) remain scarce. In this study, we evaluated survival rates and their associations with clinical factors within the context of the Brazilian Unified Health System. Data from 86 patients aged 0-19 years, diagnosed with T-ALL at one of four pediatric oncology reference centers of the Brazilian Unified Health System, were included in the study. Clinical, demographic, and laboratory variables were collected through a retrospective analysis of medical records. Cohort survival rates revealed that the 5-year overall survival probability (pOS) and event-free survival probability (pEFS) for patients with T-ALL were 47% (37.3-59.3) and 43.2% (33.5-55.7), respectively, with infection being the main cause of death (69.4%). In both bivariate and multivariate analyses, the presence of adenomegaly at diagnosis was associated with lower pOS and pEFS. In addition, the GBTLI-HR protocol achieved the highest pOS (70.0%), compared to the 35.0% and 32.0% observed with the ALL IC-BFM 2002-HR and ALL IC-BFM 2009-HR protocols, respectively. This reinforces the need for context-specific adaptations of intensive treatment protocols in LMICs. This study offers valuable insights into the clinical and demographic characteristics of patients with T-ALL from Brazil, highlighting substantially higher mortality rates than those reported in HICs, primarily attributed to high infection rates.
2026-08-07 | Synergistic apoptotic induction in acute lymphoblastic leukemia cells: exploring the role of EAAT1 inhibition by UCPH-101 in combination with asparaginase.
Despite advances in treating acute lymphoblastic leukemia (ALL), resistance to asparaginase (ASNase) remains a major clinical hurdle. Recent evidence suggests that leukemic cells may evade ASNase-induced cytotoxicity by upregulating the glutamate/aspartate transporter EAAT1 (SLC1A3). This study aimed to evaluate whether pharmacological inhibition of EAAT1 using UCPH-101 could enhance the inhibitory effects of ASNase in T-ALL models. Using patient-derived samples and established T-ALL cell lines (MOLT-4 and Jurkat) we assessed the effects of ASNase and UCPH-101, both alone and in combination. Combinations were designed based on IC50-based fixed-ratio dosing, including sub-IC50 and supra-IC50 concentrations. Effects on cell viability, apoptosis, and apoptosis related gene expression were evaluated using standardized in vitro assays. Synergy was evaluated using the combination index (CI) method on the Chou-Talalay model. Synergy analysis based on CI values revealed synergistic interactions (CI < 1) at sub and supra IC50 concentrations of both agents in MOLT-4 and Jurkat cells. Dual targeting of amino acid metabolism through ASNase and EAAT1 inhibition resulted in significantly reduced cell viability and increased apoptotic cell death compared to controls. Combinatorial treatment led to significant alterations in the expression of key apoptotic regulators, suggesting a disruption of metabolic adaptation mechanisms in both leukemic cell lines. These findings demonstrate that EAAT1 inhibition augments ASNase anti-leukemic activity in preclinical ALL models, revealing a metabolic vulnerability that can be exploited therapeutically. The mechanistic insights reported herein support further exploration of EAAT1-targeted strategies to improve outcomes in T-ALL.
2026-08-04 | Supplementary Figure 7 from PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4
<p>Supplementary Figure 7. PAMD-Ch17 induces mitochondrial dysfunction in Molt-4 Cells.</p>
2026-08-04 | Data from PAMD-Ch17, a Polymeric Analog of Plerixafor, Induces Mitochondrial Dysfunction in T-ALL Cells Independent of CXCR4
<div>Abstract<p>PAMD-Ch17 is a polymer composed of the CXCR4 inhibitor AMD3100/Plerixafor with a cholesterol modification. In previous work, we showed that PAMD-Ch17, but not AMD3100, induces cell death and differentiation in mouse acute myeloid leukemia cells. To investigate the mechanism of PAMD-Ch17’s novel antileukemic effects, we tested PAMD-Ch17 against a panel of human leukemia cell lines and found that PAMD-Ch17 is effective against a variety of acute leukemias, with T-cell acute lymphoblastic leukemia (T-ALL) cell lines being highly sensitive. Surprisingly, <i>CXCR4</i> knockout T-ALL cells were equally sensitive to PAMD-Ch17. Using a fluorescently tagged PAMD-Ch17, we found that the drug colocalized to mitochondria. We also found that PAMD-Ch17 induced changes in the expression of genes related to mitochondrial function, increased levels of mitochondrial superoxide, and decreased mitochondrial membrane potential. Using Seahorse assays, we found that PAMD-Ch17 decreased baseline oxygen consumption, ATP production, and proton leakage. In addition, we identified ATP synthase subunits as binding partners of PAMD-Ch17 and showed that the polymer, but not AMD3100, inhibited ATP synthase activity. In mouse primary T-ALL, but not healthy bone marrow cells, PAMD-Ch17 induced both mitochondrial superoxide and cell death. Using human bone marrow organoids, we found that PAMD-Ch17 induced mitochondrial superoxide and cell death in T-ALL cells from patients, but not in healthy stromal and hematopoietic cells. Collectively, our results indicate that PAMD-Ch17 has antileukemic effects against T-ALL cells but not healthy cells, likely mediated through a CXCR4-independent, mitochondrial-based mechanism. These findings support the further development of PAMDs as potential therapeutics for patients with T-ALL.</p></div>
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