Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL
| Autor: | Jon C. Aster, Noori Sotudeh, Jens G. Lohr, David T. Teachey, Guangwu Guo, Monica S. Nair, Tushara Vijaykumar, Praveen Anand, Huiyoung Yun, Anna Jollyette Rogers, Daniel J. DeAngelo, Yotam Drier, Andrew E. Place, Sayalee Potdar, Julia Frede, Tiffaney Vincent, Andrew A. Lane, Madhu M. Ouseph, Amy Guillaumet-Adkins, Jake A. Kloeber, Randi Isenhart, Lewis B. Silverman, Bradley E. Bernstein, Leili Niu, Marian H. Harris, Birgit Knoechel, Valeriya Dimitrova |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Lymphoid Neoplasia Cell cycle checkpoint Tumor Suppressor Proteins Immunology Cell Biology Hematology Cell cycle Biology Precursor T-Cell Lymphoblastic Leukemia-Lymphoma medicine.disease Biochemistry 03 medical and health sciences Leukemia 030104 developmental biology 0302 clinical medicine Immune system 030220 oncology & carcinogenesis Acute lymphocytic leukemia Cancer cell medicine Cancer research Humans Stem cell Transcription factor |
| Zdroj: | Blood |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2019004547 |
| Popis: | Lineage plasticity and stemness have been invoked as causes of therapy resistance in cancer, because these flexible states allow cancer cells to dedifferentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed/refractory early T-cell progenitor acute lymphoblastic leukemia (ETP-ALL) carrying activating NOTCH1 mutations via full-length single-cell RNA sequencing (scRNA-seq) of malignant and microenvironmental cells. We identified 2 highly distinct stem-like states that critically differed with regard to cell cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrated Notch activation and were effectively eliminated in patients by Notch inhibition, whereas slow-cycling stem-like cells were Notch independent and rather relied on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we found that both stem-like states could differentiate into a more mature leukemia state with prominent immunomodulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promoted an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that expressed HAVCR2, the cognate receptor for LGALS9. Our study identified complex interactions between signaling programs, cellular plasticity, and immune programs that characterize ETP-ALL, illustrating the multidimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem seem most promising to successfully eliminate tumor cells that escape treatment through coexisting transcriptional programs. |
| Databáze: | OpenAIRE |
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