Ye Min, Zhang Hong, Yang Henry, Koche Richard, Staber Philipp B, Cusan Monica, Levantini Elena, Welner Robert S, Bach Christian S, Zhang Junyan, Krivtsov Andrei V, Armstrong Scott A, Tenen Daniel G
Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
Cancer Science Institute, National University of Singapore, Singapore, 117599.
Cell Stem Cell. 2015 Nov 5;17(5):611-23. doi: 10.1016/j.stem.2015.08.011. Epub 2015 Sep 24.
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.
急性髓系白血病（AML）相关致癌基因的突变通常发生在造血干细胞（HSC）中，并促进白血病干细胞（LSC）表型的获得。然而，由于LSC通常具有谱系受限祖细胞的特征，分化状态对LSC转化的相对贡献尚不清楚。利用小鼠MLL-AF9和MOZ-TIF2 AML模型，我们发现髓系向粒细胞巨噬细胞祖细胞（GMP）的分化对于LSC的产生至关重要。通过缺失谱系受限转录因子C/EBPa破坏GMP形成，可阻断正常粒细胞形成并阻止AML的起始。然而，用炎性细胞因子恢复C/EBPa突变体中的髓系分化可重建AML转化能力。对GMP进行基因组分析，包括结合ATAC-seq进行基因表达和H3K79me2谱分析，揭示了一个允许激活GMP和LSC共有的最小转录程序的基因组环境。这些发现共同表明，髓系分化是LSC形成和AML发展的先决条件，为治疗开发提供了见解。
