Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.

TitleSingle-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL.
Publication TypeJournal Article
Year of Publication2021
AuthorsAnand P, Guillaumet-Adkins A, Dimitrova V, Yun H, Drier Y, Sotudeh N, Rogers A, Ouseph MM, Nair M, Potdar S, Isenhart R, Kloeber JA, Vijaykumar T, Niu L, Vincent T, Guo G, Frede J, Harris MH, Place AE, Silverman LB, Teachey DT, Lane AA, DeAngelo DJ, Aster JC, Bernstein BE, Lohr JG, Knoechel B
Date Published2021 May 06

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.

Alternate JournalBlood
PubMed ID33227818
PubMed Central IDPMC8109012
Grant ListK08 CA191026 / CA / NCI NIH HHS / United States
K08 CA191091 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
Related Faculty: 
Madhu Ouseph, M.D., Ph.D.

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