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PMID: 21741595 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Cell of origin in AML: susceptibility to MN1-induced transformation is regulated by the MEIS1/AbdB-like HOX protein complex.

Cancer cell ·Vol. 20 ·No. 1 ·2011-07-12 ·Pages 39-52

Heuser M, Yun H, Berg T, Yung E, Argiropoulos B, Kuchenbauer F, Park G, Hamwi I, Palmqvist L, Lai CK, Leung M, Lin G, Chaturvedi A, Thakur BK, Iwasaki M, Bilenky M, Thiessen N, Robertson G, Hirst M, Kent D, Wilson NK, Göttgens B, Eaves C, Cleary ML, Marra M, Ganser A, Humphries RK

Abstract

Pathways defining susceptibility of normal cells to oncogenic transformation may be valuable therapeutic targets. We characterized the cell of origin and its critical pathways in MN1-induced leukemias. Common myeloid (CMP) but not granulocyte-macrophage progenitors (GMP) could be transformed by MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that MN1-leukemogenicity required the MEIS1/AbdB-like HOX-protein complex. ChIP-sequencing identified common target genes of MN1 and MEIS1 and demonstrated identical binding sites for a large proportion of their chromatin targets. Transcriptional repression of MEIS1 targets in established MN1 leukemias demonstrated antileukemic activity. As MN1 relies on but cannot activate expression of MEIS1/AbdB-like HOX proteins, transcriptional activity of these genes determines cellular susceptibility to MN1-induced transformation and may represent a promising therapeutic target.

MeSH Terms
Animals Cell Transformation, Neoplastic/metabolism,pathology Gene Expression Profiling Gene Expression Regulation, Leukemic Genes, Dominant/genetics Granulocyte-Macrophage Progenitor Cells/metabolism,pathology Homeodomain Proteins/metabolism Humans Leukemia, Myeloid, Acute/genetics,pathology Mice Mice, Inbred C57BL Models, Biological Multiprotein Complexes/metabolism Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins/metabolism Promoter Regions, Genetic/genetics Protein Binding Tumor Suppressor Proteins/metabolism
Chemicals
Homeodomain Proteins MEIS1 protein, human Meis1 protein, mouse Multiprotein Complexes Myeloid Ecotropic Viral Integration Site 1 Protein Neoplasm Proteins Tumor Suppressor Proteins
Authors & Affiliations
27 authors, click to expand affiliations / ORCID
Heuser Michael
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Yun Haiyang
Berg Tobias
Yung Eric
Argiropoulos Bob
Kuchenbauer Florian
Park Gyeongsin
Hamwi Iyas
Palmqvist Lars
Lai Courteney K
Leung Malina
Lin Grace
Chaturvedi Anuhar
Thakur Basant Kumar
Iwasaki Masayuki
Bilenky Mikhail
Thiessen Nina
Robertson Gordon
Hirst Martin
Kent David
Wilson Nicola K
Göttgens Bertie
Eaves Connie
Cleary Michael L
Marra Marco
Ganser Arnold
Humphries R Keith
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.06.020
Published
2011-07-12
Pages
39-52
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3951989
Subset
IM
Grants
CIHR · 92093-1 · Canada
Medical Research Council · G0800784 · United Kingdom
National Centre for the Replacement, Refinement and Reduction of Animals in Research · G0900729/1 · United Kingdom
Databases
GEO
GSE22923
External Links
PubMed source DOI: 10.1016/j.ccr.2011.06.020 PMC Full Text View journal details
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