Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: The molecular mechanism defining susceptibility of normal cells to oncogenic transformation may be a valuable therapeutic target. We characterized the cell of origin and its critical pathways in MN1 leukemias. Common myeloid (CMP), but not granulocyte-macrophage progenitors (CMP) could be transformed by constitutively overexpressed MN1. Complementation studies of CMP-signature genes in GMPs demonstrated that leukemogenicity of MN1 required the MEIS1/abdB-like HOX protein complex. Colocalization studies by ChIP-seq identified common chromatin targets of MN1 and MEIS1 that were associated with open chromatin and transcriptional activation. Transcriptional repression of MEIS1 target sites in established MN1 leukemias had antileukemic activity. As MN1 relies on but can not activate expression of MEIS1/abdB-like HOX proteins, transcriptional activity of these genes determines which cell is the cell of origin in MN1 leukemia. We have showed at the single cell level that CMPs, but not GMPs, are susceptible to MN1-induced transformation. To identify transcriptional differences between CMPs and GMPs that may explain this difference in susceptibilities to MN1 transformation we produced gene expression profiles (two biological replicates in each experimental arm) of bone marrow cells from MN1 leukemic mice and mature myeloid bone marrow cells (Gr1+/CD11b+) from healthy mice and compared those to already published gene expression profiles of CMPs and GMPs (Krivtsov, A.V., et al. (2006). Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818-822).

ORGANISM(S): Mus musculus

SUBMITTER: Lars Palmqvist

PROVIDER: E-GEOD-22923 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Heuser Michael M Yun Haiyang H Berg Tobias T Yung Eric E Argiropoulos Bob B Kuchenbauer Florian F Park Gyeongsin G Hamwi Iyas I Palmqvist Lars L Lai Courteney K CK Leung Malina M Lin Grace G Chaturvedi Anuhar A Thakur Basant Kumar BK Iwasaki Masayuki M Bilenky Mikhail M Thiessen Nina N Robertson Gordon G Hirst Martin M Kent David D Wilson Nicola K NK Göttgens Bertie B Eaves Connie C Cleary Michael L ML Marra Marco M Ganser Arnold A Humphries R Keith RK

Cancer cell 20110701 1

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 an ...[more]

PMID: 21741595

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Dataset Information

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

Publications

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

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