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.
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.
authors: Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors: Yue
authors: Y
authors: Zhang
authors: Xiaomei
authors: X
authors: Yan
authors: Goro
authors: G
authors: Sashida
authors: Xinghui
authors: X
authors: Zhao
authors: Yalan
authors: Y
authors: Rao
authors: Susumu
authors: S
authors: Goyama
authors: Susan P
authors: SP
authors: Whitman
authors: Nicholas
authors: N
authors: Zorko
authors: Kelsie
authors: K
authors: Bernot
authors: Rajeana M
authors: RM
authors: Conway
authors: David
authors: D
authors: Witte
authors: Qian-Fei
authors: QF
authors: Wang
authors: Daniel G
authors: DG
authors: Tenen
authors: Zhijian
authors: Z
authors: Xiao
authors: Guido
authors: G
authors: Marcucci
authors: James C
authors: JC
authors: Mulloy
authors: H Leighton
authors: HL
authors: Grimes
authors: Michael A
authors: MA
authors: Caligiuri
authors: Gang
authors: G
authors: Huang
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D060965:Clonal Evolution / Q000235:genetics; D020440:Gene Duplication / Q000502:physiology; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism / Q000502:physiology*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology*; D020080:Tandem Repeat Sequences / Q000235:genetics
chemical_list: C497422:KMT2A protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase