Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia

Ye M, Zhang H, Yang H, Koche R, Staber PB, Cusan M, Levantini E, Welner RS, Bach C, Zhang J, Krivtsov AV, Armstrong SA, Tenen DG (2015)

Publication Type: Journal article

Publication year: 2015

Journal

Cell Stem Cell Elsevier (Cell Press)

Book Volume: 17

Pages Range: 611-23

Journal Issue: 5

DOI: 10.1016/j.stem.2015.08.011

Abstract

Mutations in acute myeloid leukemia (AML)-associated oncogenes often arise in hematopoietic stem cells (HSCs) and promote acquisition of leukemia stem cell (LSC) phenotypes. However, as LSCs often share features of lineage-restricted progenitors, the relative contribution of differentiation status to LSC transformation is unclear. Using murine MLL-AF9 and MOZ-TIF2 AML models, we show that myeloid differentiation to granulocyte macrophage progenitors (GMPs) is critical for LSC generation. Disrupting GMP formation by deleting the lineage-restricted transcription factor C/EBPa blocked normal granulocyte formation and prevented initiation of AML. However, restoring myeloid differentiation in C/EBPa mutants with inflammatory cytokines reestablished AML transformation capacity. Genomic analyses of GMPs, including gene expression and H3K79me2 profiling in conjunction with ATAC-seq, revealed a permissive genomic environment for activation of a minimal transcription program shared by GMPs and LSCs. Together, these findings show that myeloid differentiation is a prerequisite for LSC formation and AML development, providing insights for therapeutic development.

Authors with CRIS profile

Christian Bach Department of Medicine 5 – Haematology and Oncology

Involved external institutions

Harvard University US United States (USA) (US) Memorial Sloan Kettering Cancer Center US United States (USA) (US) National University of Singapore (NUS) SG Singapore (SG)

How to cite

APA:

Ye, M., Zhang, H., Yang, H., Koche, R., Staber, P.B., Cusan, M.,... Tenen, D.G. (2015). Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia. Cell Stem Cell, 17(5), 611-23. https://dx.doi.org/10.1016/j.stem.2015.08.011

MLA:

Ye, Min, et al. "Hematopoietic Differentiation Is Required for Initiation of Acute Myeloid Leukemia." Cell Stem Cell 17.5 (2015): 611-23.

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