한빛사논문
- 조회1,062
Praveen Anand#1,2,3, Amy Guillaumet-Adkins#2,3, Valeriya Dimitrova#2,3, Huiyoung Yun#2,3, Yotam Drier#2,4,5, Noori Sotudeh3, Anna Rogers3, Madhu M. Ouseph6, Monica Nair3, Sayalee Potdar3, Randi Isenhart3, Jake A. Kloeber3, Tushara Vijaykumar1, Leili Niu3, Tiffaney Vincent7, Guangwu Guo1,2,3, Julia Frede1,2, Marian H. Harris8, Andrew E. Place3,9, Lewis B. Silverman3,9, David T. Teachey7, Andrew A. Lane1,2,10, Daniel J. DeAngelo1,10, Jon C. Aster6,10, Bradley E. Bernstein2,4,10, Jens G. Lohr*±1,2,10, Birgit Knoechel*±2,3,9,10
1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
2. Broad Institute of MIT and Harvard, Cambridge, MA, USA.
3. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
4. Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA.
5. Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
6. Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
7. Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA.
8. Department of Pathology, Boston Children’s Hospital, Boston, MA 02115, USA.
9. Division of Hematology/Oncology, Department of Medicine, Boston Children’s Hospital,
MA, USA.
10. Harvard Medical School, Boston, MA, USA.
#These authors contributed equally to the work.
±These authors contributed equally to the work.
*Corresponding authors
Abstract
Lineage plasticity and stemness have been invoked as the cause of therapy resistance in cancer, as these flexible states allow cancer cells to de-differentiate and alter their dependencies. We investigated such resistance mechanisms in relapsed / refractory early T-cell progenitor acute lymphoblastic leukemia carrying activating NOTCH1 mutations, by full-length single cell RNA sequencing of malignant and microenvironmental cells. We identified two highly distinct stem-like states that critically differ in their cell-cycle and oncogenic signaling. Fast-cycling stem-like leukemia cells demonstrate Notch activation and are effectively eliminated in patients by Notch inhibition, while slow cycling stem-like cells are Notch-independent but rather rely on PI3K signaling, likely explaining the poor efficacy of Notch inhibition in this disease. Remarkably, we find that both stem-like states can differentiate into a more mature leukemia state with prominent immune-modulatory functions, including high expression of the LGALS9 checkpoint molecule. These cells promote an immunosuppressive leukemia ecosystem with clonal accumulation of dysfunctional CD8+ T cells that express HAVCR2, the cognate receptor for LGALS9. Our study identifies complex interactions between signaling programs, cellular plasticity and immune programs that characterize T-ALL and illustrates the multi-dimensionality of tumor heterogeneity. In this scenario, combination therapies targeting diverse oncogenic states and the immune ecosystem appear most promising to successfully eliminate tumor cells that escape treatment through co-existing transcriptional programs.
논문정보
- Research article
- 2020년 11월 (BRIC 등록일 2020-12-18)
- 국외 연구진
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