Document Detail


CBFbeta-SMMHC slows proliferation of primary murine and human myeloid progenitors.
MedLine Citation:
PMID:  15815715     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CBFbeta-SMMHC is expressed in 8% of acute myeloid leukemias and inhibits AML1/RUNX1. In this study, murine marrow or human CD34(+) cells were transduced with retroviral or lentiviral vectors expressing CBFbeta-SMMHC or two mutant variants. CBFbeta-SMMHC reduced murine or human myeloid cell proliferation three- to four-fold in liquid culture relative to empty vector-transduced cells, during a period when vector-transduced cells accumulated five-fold and human cells 20-fold. CBFbeta-SMMHC decreased the formation of myeloid, but not erythroid, colonies two- to four-fold, and myeloid colonies expressing CBFbeta-SMMHC were markedly reduced in size. However, CBFbeta-SMMHC did not slow differentiation to granulocytes or monocytes. Neither CBFbeta-SMMHC(Delta2-11), which does not bind AML1, nor CBFbeta-SMMHC(DeltaACD), which does not multimerize or efficiently bind corepressors, slowed proliferation or reduced myeloid colonies. CBFbeta-SMMHC increased the G1/S ratio 1.4-fold. AML1 had an effect opposite to CBFbeta-SMMHC, stimulating proliferation of murine myeloid progenitors 2.0-fold in liquid culture. Thus, CBFbeta-SMMHC directly inhibits the proliferation of normal myeloid progenitors via inhibition of AML1 and dependent upon the integrity of its assembly competence domain. These findings support the development of therapeutics that target the ability of CBFbeta-SMMHC to interact with AML1 or to multimerize via its assembly competence domain.
Authors:
J D'Costa; S Chaudhuri; C I Civin; A D Friedman
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Leukemia     Volume:  19     ISSN:  0887-6924     ISO Abbreviation:  Leukemia     Publication Date:  2005 Jun 
Date Detail:
Created Date:  2005-05-24     Completed Date:  2005-06-30     Revised Date:  2013-03-04    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  England    
Other Details:
Languages:  eng     Pagination:  921-9     Citation Subset:  IM    
Affiliation:
Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
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MeSH Terms
Descriptor/Qualifier:
Acute Disease
Animals
Cell Differentiation
Cell Division
Core Binding Factor Alpha 2 Subunit
DNA-Binding Proteins / genetics
Female
Fetal Blood / cytology
Genetic Therapy / methods*
Hematopoietic Stem Cells / pathology*,  physiology*
Humans
Lentivirus / genetics
Leukemia, Myeloid / pathology*,  physiopathology,  therapy*
Mice
Mice, Inbred C57BL
Oncogene Proteins, Fusion / genetics*
Proto-Oncogene Proteins / genetics
Retroviridae / genetics
Transcription Factors / genetics
Transduction, Genetic
Grant Support
ID/Acronym/Agency:
R01 CA098805/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/CBFbeta-MYH11 fusion protein; 0/Core Binding Factor Alpha 2 Subunit; 0/DNA-Binding Proteins; 0/Oncogene Proteins, Fusion; 0/Proto-Oncogene Proteins; 0/RUNX1 protein, human; 0/Runx1 protein, mouse; 0/Transcription Factors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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