Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells

Yue Zhang, Xiaomei Yan, Goro Sashida, Xinghui Zhao, Yalan Rao, Susumu Goyama, Susan P. Whitman, Nicholas Zorko, Kelsie Bernot, Rajeana M. Conway, David Witte, Qian Fei Wang, Daniel G. Tenen, Zhijian Xiao, Guido Marcucci, James C. Mulloy, H. Leighton Grimes, Michael A. Caligiuri, Gang Huang

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

One mechanism for disrupting the MLL gene in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) is through partial tandem duplication (MLL-PTD); however, the mechanism by which MLL-PTD contributes to MDS and AML development and maintenance is currently unknown. Herein, we investigated hematopoietic stem/progenitor cell (HSPC) phenotypes of Mll-PTD knock-in mice. Although HSPCs (Lin -Sca1 +Kit + (LSK)/SLAM + and LSK) in Mll PTD/WT mice are reduced in absolute number in steady state because of increased apoptosis, they have a proliferative advantage in colony replating assays, CFU-spleen assays, and competitive transplantation assays over wild-type HSPCs. The Mll PTD/WT-derived phenotypic short-term (ST)-HSCs/multipotent progenitors and granulocyte/ macrophage progenitors have self-renewal capability, rescuing hematopoiesis by giving rise to long-term repopulating cells in recipient mice with an unexpected myeloid differentiation blockade and lymphoid-lineage bias. However, Mll PTD/WT HSPCs never develop leukemia in primary or recipient mice, suggesting that additional genetic and/or epigenetic defects are necessary for full leukemogenic transformation. Thus, the Mll-PTD aberrantly alters HSPCs, enhances self-renewal, causes lineage bias, and blocks myeloid differentiation. These findings provide a framework by which we can ascertain the underlying pathogenic role of MLL-PTD in the clonal evolution of human leukemia, which should facilitate improved therapies and patient outcomes.

Original languageEnglish (US)
Pages (from-to)1118-1129
Number of pages12
JournalBlood
Volume120
Issue number5
DOIs
StatePublished - Aug 2 2012

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