PMID- 24894773
OWN - NLM
STAT- MEDLINE
DCOM- 20141006
LR  - 20211021
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 124
IP  - 3
DP  - 2014 Jul 17
TI  - NrasG12D oncoprotein inhibits apoptosis of preleukemic cells expressing 
      Cbfbeta-SMMHC via activation of MEK/ERK axis.
PG  - 426-36
LID - 10.1182/blood-2013-12-541730 [doi]
AB  - Acute myeloid leukemia (AML) results from the activity of driver mutations that 
      deregulate proliferation and survival of hematopoietic stem cells (HSCs). The 
      fusion protein CBFbeta-SMMHC impairs differentiation in hematopoietic stem and 
      progenitor cells and induces AML in cooperation with other mutations. However, 
      the combined function of CBFbeta-SMMHC and cooperating mutations in preleukemic 
      expansion is not known. Here, we used Nras(LSL-G12D); Cbfb(56M) knock-in mice to 
      show that allelic expression of oncogenic Nras(G12D) and Cbfbeta-SMMHC increases 
      survival of preleukemic short-term HSCs and myeloid progenitor cells and 
      maintains the differentiation block induced by the fusion protein. Nras(G12D) and 
      Cbfbeta-SMMHC synergize to induce leukemia in mice in a cell-autonomous manner, with 
      a shorter median latency and higher leukemia-initiating cell activity than that 
      of mice expressing Cbfbeta-SMMHC. Furthermore, Nras(LSL-G12D); Cbfb(56M) leukemic 
      cells were sensitive to pharmacologic inhibition of the MEK/ERK signaling 
      pathway, increasing apoptosis and Bim protein levels. These studies demonstrate 
      that Cbfbeta-SMMHC and Nras(G12D) promote the survival of preleukemic myeloid 
      progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define 
      Nras(LSL-G12D); Cbfb(56M) mice as a valuable genetic model for the study of 
      inversion(16) AML-targeted therapies.
CI  - (c) 2014 by The American Society of Hematology.
FAU - Xue, Liting
AU  - Xue L
AD  - Program in Gene Function and Expression, University of Massachusetts Medical 
      School, Worcester MA; and.
FAU - Pulikkan, John A
AU  - Pulikkan JA
AD  - Program in Gene Function and Expression, University of Massachusetts Medical 
      School, Worcester MA; and.
FAU - Valk, Peter J M
AU  - Valk PJ
AD  - Erasmus University Medical Center, Rotterdam, The Netherlands.
FAU - Castilla, Lucio H
AU  - Castilla LH
AD  - Program in Gene Function and Expression, University of Massachusetts Medical 
      School, Worcester MA; and.
LA  - eng
GR  - R01 CA096983/CA/NCI NIH HHS/United States
GR  - R01 CA140398/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 - 20140603
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Apoptosis Regulatory Proteins)
RN  - 0 (Bcl-2-Like Protein 11)
RN  - 0 (Bcl2l11 protein, mouse)
RN  - 0 (CBFbeta-MYH11 fusion protein)
RN  - 0 (Membrane Proteins)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Oncogene Proteins, Fusion)
RN  - 0 (Proto-Oncogene Proteins)
RN  - EC 3.6.5.2 (Monomeric GTP-Binding Proteins)
RN  - EC 3.6.5.2 (Nras protein, mouse)
SB  - IM
MH  - Animals
MH  - Apoptosis
MH  - Apoptosis Regulatory Proteins/metabolism
MH  - Bcl-2-Like Protein 11
MH  - Cell Survival
MH  - Gene Knock-In Techniques
MH  - Leukemia, Experimental/etiology/metabolism/pathology
MH  - Leukemia, Myeloid, Acute/etiology/metabolism/pathology
MH  - MAP Kinase Signaling System
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Monomeric GTP-Binding Proteins/genetics/*metabolism
MH  - Mutation, Missense
MH  - Neoplastic Stem Cells/metabolism/pathology
MH  - Oncogene Proteins/genetics/*metabolism
MH  - Oncogene Proteins, Fusion/genetics/*metabolism
MH  - Preleukemia/genetics/*metabolism/*pathology
MH  - Proto-Oncogene Proteins/metabolism
PMC - PMC4102713
EDAT- 2014/06/05 06:00
MHDA- 2014/10/07 06:00
PMCR- 2015/07/17
CRDT- 2014/06/05 06:00
PHST- 2014/06/05 06:00 [entrez]
PHST- 2014/06/05 06:00 [pubmed]
PHST- 2014/10/07 06:00 [medline]
PHST- 2015/07/17 00:00 [pmc-release]
AID - S0006-4971(20)39975-4 [pii]
AID - 2013/541730 [pii]
AID - 10.1182/blood-2013-12-541730 [doi]
PST - ppublish
SO  - Blood. 2014 Jul 17;124(3):426-36. doi: 10.1182/blood-2013-12-541730. Epub 2014 
      Jun 3.