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Cell of Origin in AML: Susceptibility to MN1-Induced Transformation Is Regulated by the MEIS1/AbdB-like HOX Protein Complex

2011; Cell Press; Volume: 20; Issue: 1 Linguagem: Inglês

10.1016/j.ccr.2011.06.020

1878-3686

Michael Heuser, Haiyang Yun, Tobias Berg, Eric Yung, Bob Argiropoulos, Florian Kuchenbauer, Gyeongsin Park, Iyas Hamwi, Lars Palmqvist, Courteney K. Lai, Malina Leung, Grace Lin, Anuhar Chaturvedi, Basant Kumar Thakur, Masayuki Iwasaki, Mikhail Bilenky, Nina Thiessen, Gordon Robertson, Martin Hirst, David G. Kent, Nicola K. Wilson, Berthold Göttgens, Connie J. Eaves, Michael L. Cleary, Marco A. Marra, Arnold Ganser, R. Keith Humphries,

Histone Deacetylase Inhibitors Research

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.PaperClip/cms/asset/2f5e9c75-4908-4781-8147-5a2550e8cdf3/mmc9.mp3Loading ...(mp3, 5.26 MB) Download audio