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
Book Volume: 17
Pages Range: 611-23
Journal Issue: 5
DOI: 10.1016/j.stem.2015.08.011
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.
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://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.
BibTeX: Download