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

Praveen Anand, Amy Guillaumet-Adkins, Valeriya Dimitrova, Huiyoung Yun, Yotam Drier, Noori Sotudeh, Anna Rogers, Madhu M. Ouseph, Monica Nair, Sayalee Potdar, Randi Isenhart, Jake A. Kloeber, Tushara Vijaykumar, Leili Niu, Tiffaney Vincent, Guangwu Guo, Julia Frede, Marian H. Harris, Andrew E. Place, Lewis B. SilvermanDavid T. Teachey, Andrew A. Lane, Daniel J. DeAngelo, Jon C. Aster, Bradley E. Bernstein, Jens G. Lohr*, Birgit Knoechel*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)2463-2480
Number of pages18
JournalBlood
Volume137
Issue number18
DOIs
StatePublished - 6 May 2021

Bibliographical note

Publisher Copyright:
© 2021 American Society of Hematology

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