Identification and targeting of treatment resistant progenitor populations in T-cell Acute Lymphoblastic Leukemia.

Autor:	Tan K; Children's Hospital of Philadelphia., Xu J; University of Pennsylvania., Chen C; The Children's Hospital of Philadelphia., Vincent T; Children's Hospital of Philadelphia., Pölönen P; St. Jude Children's Research Hospital., Hu J; St. Jude Children's Research Hospital., Yoshimura S; St. Jude Children's Research Hospital., Yu W; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Sussman J; University of Pennsylvania., Chen CH; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Li E; Divsion of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Diorio C; Children's Hospital of Philadelphia., Shraim R; Children's Hospital of Philadelphia., Newman H; Children's Hospital of Philadelphia., Uppuluri L; Children's Hospital of Philadelphia., Li A; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Chen G; University of Pennsylvania., Bandyopadhyay S; The Children's Hospital of Philadelphia., Wu D; Graduate Group in Genomics and Computational Biology, Perelman School of Medicine., Ding YY; Johns Hopkins University School of Medicine., Xu J; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Lim T; Perelman School of Medicine, University of Pennsylvania., Hsu M; Perelman School of Medicine, University of Pennsylvania., Thadi A; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Ahn KJ; Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia., Wu CY; Graduate Group in Genomics and Computational Biology, Perelman School of Medicine., Peng J; University of Pennsylvania., Sun Y; University of Pennsylvania., Wang A; Graduate Group in Genomics and Computational Biology, Perelman School of Medicine, University of Pennsylvania., Mehta R; Graduate Group in Cell & Molecular Biolgy, Perelman School of Medicine, University of Pennsylvania., Frank D; University of Pennsylvania., Meyer L; The Ben Town Center for Childhood Cancer Research, Seattle Children's Hospital., Loh M; Seattle Children's Hospital., Raetz E; NYU Langone Health., Chen Z; University of Florida., Wood B; Children's Hospital Los Angeles., Devidas M; St. Jude Children's Research Hospital., Dunsmore K; Division of Oncology, University of Virginia Children's Hospital, Charlottesville., Winter S; Children's Minnesota Research Institute., Chang TC; St. Jude Children's Research Hospital., Wu G; St Jude Children's Research Hospital., Pounds S; St. Jude Children's Research Hospital., Zhang N; University of Pennsylvania., Carroll W; NYU Langone Health., Hunger S; Children's Hospital of Philadelphia., Bernt K; Children's Hospital of Philadelphia., Yang J; St. Jude Children's Research Hospital., Mullighan C; St. Jude Children's Research Hospital., Teachey D; University of Pennsylvania, Children's Hospital of Philadelphia.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2023 Oct 30. Date of Electronic Publication: 2023 Oct 30.
DOI:	10.21203/rs.3.rs-3487715/v1
Abstrakt:	Refractoriness to initial chemotherapy and relapse after remission are the main obstacles to cure in T-cell Acute Lymphoblastic Leukemia (T-ALL). Biomarker guided risk stratification and targeted therapy have the potential to improve outcomes in high-risk T-ALL; however, cellular and genetic factors contributing to treatment resistance remain unknown. Previous bulk genomic studies in T-ALL have implicated tumor heterogeneity as an unexplored mechanism for treatment failure. To link tumor subpopulations with clinical outcome, we created an atlas of healthy pediatric hematopoiesis and applied single-cell multiomic (CITE-seq/snATAC-seq) analysis to a cohort of 40 cases of T-ALL treated on the Children's Oncology Group AALL0434 clinical trial. The cohort was carefully selected to capture the immunophenotypic diversity of T-ALL, with early T-cell precursor (ETP) and Near/Non-ETP subtypes represented, as well as enriched with both relapsed and treatment refractory cases. Integrated analyses of T-ALL blasts and normal T-cell precursors identified a bone-marrow progenitor-like (BMP-like) leukemia sub-population 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 within two independent patient cohorts using bulk RNA-sequencing data from over 1300 patients. We defined the mutational landscape of BMP-like T-ALL, finding that NOTCH1 mutations additively drive T-ALL blasts away from the BMP-like state. We transcriptionally matched BMP-like blasts to early thymic seeding progenitors that have low NR3C1 expression and high stem cell gene expression, corresponding to a corticosteroid and conventional cytotoxic resistant phenotype we observed in ex vivo drug screening. To identify novel targets for BMP-like blasts, we performed in silico and in vitro drug screening against the BMP-like signature and prioritized BMP-like overexpressed cell-surface (CD44, ITGA4, LGALS1) and intracellular proteins (BCL-2, MCL-1, BTK, NF-κB) as candidates for precision targeted therapy. We established patient derived xenograft models of BMP-high and BMP-low leukemias, which revealed vulnerability of BMP-like blasts to apoptosis-inducing agents, TEC-kinase inhibitors, and proteasome inhibitors. Our study establishes the first multi-omic signatures for rapid risk-stratification and targeted treatment of high-risk T-ALL. Competing Interests: Competing interest: DTT received research funding from BEAM Therapeutics, NeoImmune Tech and serves on advisory boards for BEAM Therapeutics, Janssen, Servier, Sobi, and Jazz. DTT has multiple patents pending on CAR-T. The remaining authors declare that they have no competing interest.
Databáze:	MEDLINE
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