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|Title:||Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells|
|Citation:||Zhang, Y., Yan, X., Sashida, G., Zhao, X., Rao, Y., Goyama, S., Whitman, S.P., Zorko, N., Bernot, K., Conway, R.M., Witte, D., Wang, Q.-F., Tenen, D.G., Xiao, Z., Marcucci, G., Mulloy, J.C., Grimes, H.L., Caligiuri, M.A., Huang, G. (2012-08-02). Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic stem/progenitor cells. Blood 120 (5) : 1118-1129. ScholarBank@NUS Repository. https://doi.org/10.1182/blood-2012-02-412379|
|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. © 2012 by The American Society of Hematology.|
|Appears in Collections:||Staff Publications|
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