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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Hematologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Hematology (hsv//eng)

Nyckelord

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

Neoplasm Proteins

metabolism

Promoter Regions

Genetic

genetics

Protein Binding

Tumor Suppressor Proteins

metabolism

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