Similar Datasets
Project description:T-cell acute lymphoblastic leukemia (T-ALL), a malignant neoplasm of immature T cells, is a particularly aggressive leukemia with diverse subtypes and limited therapeutic options. Recent studies showed that the responsiveness of drugs in preclinical models of T-ALL is linked to the specific biological characteristics exhibited by the T-ALL subtype. In order to comprehensively explore the underlying heterogeneity of T-ALL, we performed an integrative analysis of bone marrow biopsies from newly diagnosed T-ALL patients. Leveraging a combination of cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) along with T-cell receptor sequencing (TCR-seq), we obtained a comprehensive molecular characterization of T-ALL. Our analysis uncovered a distinct subset of inflammatory T-ALLs (iT-ALLs) resembling early T-cell precursor (ETP) leukemias, characterized by enriched expression of hematopoietic stem and progenitor signatures, inflammatory gene programs, and poor survival outcomes. Furthermore, our investigation revealed a significant association between the transcription factor interferon regulatory factor 5 (IRF5) activity and the iT-ALL subgroup. Utilizing an IRF5 scoring system, we demonstrated its potential as a robust biomarker for classifying T-ALL patients and predicting disease prognosis. Our work provides a framework for identifying high-risk T-ALL patients based on the IRF5 activity and a rational for considering the inflammatory state in tailoring therapeutic interventions.
2024-12-31 | GSE234610 | GEO
Project description:T-cell acute lymphoblastic leukemia (T-ALL), a malignant neoplasm of immature T cells, is a particularly aggressive leukemia with diverse subtypes and limited therapeutic options. Recent studies showed that the responsiveness of drugs in preclinical models of T-ALL is linked to the specific biological characteristics exhibited by the T-ALL subtype. In order to comprehensively explore the underlying heterogeneity of T-ALL, we performed an integrative analysis of bone marrow biopsies from newly diagnosed T-ALL patients. Leveraging a combination of cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) along with T-cell receptor sequencing (TCR-seq), we obtained a comprehensive molecular characterization of T-ALL. Our analysis uncovered a distinct subset of inflammatory T-ALLs (iT-ALLs) resembling early T-cell precursor (ETP) leukemias, characterized by enriched expression of hematopoietic stem and progenitor signatures, inflammatory gene programs, and poor survival outcomes. Furthermore, our investigation revealed a significant association between the transcription factor interferon regulatory factor 5 (IRF5) activity and the iT-ALL subgroup. Utilizing an IRF5 scoring system, we demonstrated its potential as a robust biomarker for classifying T-ALL patients and predicting disease prognosis. Our work provides a framework for identifying high-risk T-ALL patients based on the IRF5 activity and a rational for considering the inflammatory state in tailoring therapeutic interventions.
2024-12-31 | GSE234608 | GEO
Project description:An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup
| PRJNA982126 | ENA
Project description:An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup [bulkRNA-Seq]
| PRJNA982121 | ENA
Project description:An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup [CITE-seq]
| PRJNA982124 | ENA
Project description:We assessed the molecular relationship of IG-MYC rearranged ALL with other ALL subtypes and Burkitt’s lymphoma and describe the genetic and clinical outcomes of IG-MYC rearranged ALL
2022-05-31 | GSE174248 | GEO
Project description:KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.
| S-EPMC9427775 | biostudies-literature
Project description:Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed-lineage leukemia (MLL)-rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)-positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph+ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy.
| S-EPMC2814411 | biostudies-literature
Project description:3D genome alternations can dysregulate gene expression by rewiring enhancer-promoter interactions and lead to diseases. We report integrated analyses of 3D genome alterations and differential gene expressions in 18 newly diagnosed T-lineage acute lymphoblastic leukemia (T-ALL) patients and 4 healthy controls. 3D genome organizations at the levels of compartment, topologically associated domains and loop could hierarchically classify different subtypes of T-ALL according to T cell differentiation trajectory, similar to gene expressions-based classification. Thirty-four previously unrecognized translocations and 44 translocation-mediated neo-loops are mapped by Hi-C analysis. We find that neo-loops formed in the non-coding region of the genome could potentially regulate ectopic expressions of TLX3, TAL2 and HOXA transcription factors via enhancer hijacking. Importantly, both translocation-mediated neo-loops and NUP98-related fusions are associated with HOXA13 ectopic expressions. Patients with HOXA11-A13 expressions, but not other genes in the HOXA cluster, have immature immunophenotype and poor outcomes. Here, we highlight the potentially important roles of 3D genome alterations in the etiology and prognosis of T-ALL.
| S-EPMC8211852 | biostudies-literature
Project description:Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of ALL in children. There are conflicting data on the incidence and prognosis of Ph-like ALL in adults. Patients with newly diagnosed B-cell ALL (B-ALL) who received frontline chemotherapy at MD Anderson Cancer Center underwent gene expression profiling of leukemic cells. Of 148 patients, 33.1% had Ph-like, 31.1% had Ph+, and 35.8% had other B-ALL subtypes (B-other). Within the Ph-like ALL cohort, 61% had cytokine receptor-like factor 2 (CRLF2) overexpression. Patients with Ph-like ALL had significantly worse overall survival (OS), and event-free survival compared with B-other with a 5-year survival of 23% (vs 59% for B-other, P = .006). Sixty-eight percent of patients with Ph-like ALL were of Hispanic ethnicity. The following were associated with inferior OS on multivariable analysis: age (hazard ratio [HR], 3.299; P < .001), white blood cell count (HR, 1.910; P = .017), platelet count (HR, 7.437; P = .005), and Ph-like ALL (HR, 1.818; P = .03). Next-generation sequencing of the CRLF2+ group identified mutations in the JAK-STAT and Ras pathway in 85% of patients, and 20% had a CRLF2 mutation. Within the CRLF2+ group, JAK2 mutation was associated with inferior outcomes. Our findings show high frequency of Ph-like ALL in adults, an increased frequency of Ph-like ALL in adults of Hispanic ethnicity, significantly inferior outcomes of adult patients with Ph-like ALL, and significantly worse outcomes in the CRLF2+ subset of Ph-like ALL. Novel strategies are needed to improve the outcome of these patients.
| S-EPMC5290985 | biostudies-other