PMID- 22740449
OWN - NLM
STAT- MEDLINE
DCOM- 20121025
LR  - 20211021
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 120
IP  - 5
DP  - 2012 Aug 2
TI  - Stress hematopoiesis reveals abnormal control of self-renewal, lineage bias, and 
      myeloid differentiation in Mll partial tandem duplication (Mll-PTD) hematopoietic 
      stem/progenitor cells.
PG  - 1118-29
LID - 10.1182/blood-2012-02-412379 [doi]
AB  - 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.
FAU - Zhang, Yue
AU  - Zhang Y
AD  - Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, 
      OH 45229, USA.
FAU - Yan, Xiaomei
AU  - Yan X
FAU - Sashida, Goro
AU  - Sashida G
FAU - Zhao, Xinghui
AU  - Zhao X
FAU - Rao, Yalan
AU  - Rao Y
FAU - Goyama, Susumu
AU  - Goyama S
FAU - Whitman, Susan P
AU  - Whitman SP
FAU - Zorko, Nicholas
AU  - Zorko N
FAU - Bernot, Kelsie
AU  - Bernot K
FAU - Conway, Rajeana M
AU  - Conway RM
FAU - Witte, David
AU  - Witte D
FAU - Wang, Qian-Fei
AU  - Wang QF
FAU - Tenen, Daniel G
AU  - Tenen DG
FAU - Xiao, Zhijian
AU  - Xiao Z
FAU - Marcucci, Guido
AU  - Marcucci G
FAU - Mulloy, James C
AU  - Mulloy JC
FAU - Grimes, H Leighton
AU  - Grimes HL
FAU - Caligiuri, Michael A
AU  - Caligiuri MA
FAU - Huang, Gang
AU  - Huang G
LA  - eng
GR  - R01 CA089341/CA/NCI NIH HHS/United States
GR  - CA41456/CA/NCI NIH HHS/United States
GR  - P30 DK090971/DK/NIDDK NIH HHS/United States
GR  - P50 CA140158/CA/NCI NIH HHS/United States
GR  - CA140158/CA/NCI NIH HHS/United States
GR  - P30DK090971/DK/NIDDK NIH HHS/United States
GR  - P30 CA016058/CA/NCI NIH HHS/United States
GR  - R01 CA041456/CA/NCI NIH HHS/United States
GR  - CA89341/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120626
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (KMT2A protein, human)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/genetics
MH  - Cell Lineage/genetics/physiology
MH  - *Cell Proliferation
MH  - Cells, Cultured
MH  - Clonal Evolution/genetics
MH  - Gene Duplication/physiology
MH  - Hematopoiesis/drug effects/genetics/*physiology
MH  - Hematopoietic Stem Cells/metabolism/pathology/*physiology
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Myeloid Cells/metabolism/*physiology
MH  - Myeloid-Lymphoid Leukemia Protein/*genetics
MH  - Stress, Physiological/drug effects/*physiology
MH  - Tandem Repeat Sequences/genetics
PMC - PMC3412332
EDAT- 2012/06/29 06:00
MHDA- 2012/10/26 06:00
PMCR- 2013/08/02
CRDT- 2012/06/29 06:00
PHST- 2012/06/29 06:00 [entrez]
PHST- 2012/06/29 06:00 [pubmed]
PHST- 2012/10/26 06:00 [medline]
PHST- 2013/08/02 00:00 [pmc-release]
AID - S0006-4971(20)46561-9 [pii]
AID - 2012/412379 [pii]
AID - 10.1182/blood-2012-02-412379 [doi]
PST - ppublish
SO  - Blood. 2012 Aug 2;120(5):1118-29. doi: 10.1182/blood-2012-02-412379. Epub 2012 
      Jun 26.