Myeloid maturation block by AML1-MTG16 is associated with Csf1r epigenetic downregulation.
De novo epigenetic changes at histone and DNA level that affect gene transcription in cancer may be less random than we originally thought. Leukemia fusion proteins associated with specific chromosome translocations could mechanistically determine the epigenetic fate of specific target genes critical for normal hematopoiesis. This seems to be the case with AML1-MTG16, a fusion protein resulting from the t(16;21) translocation, a hallmark of therapy-related leukemia and myelodysplastic syndrome. Here we show that AML1-MTG16 blocks both myeloid differentiation and proliferation in the 32D/WT1-mouse myeloid cell line. These biological effects can be traced to the AML1 and MTG16 moieties of the fusion protein, respectively. Further, we show that AML1-MTG16 can induce epigenetic repressive changes at the histone and DNA level of the AML1 target gene Csf1r (c-fms), encoding the macrophage colony stimulating factor receptor. We observed that, concomitant with Csf1r downregulation, 32D/WT1 cells lost the ability to undergo myeloid differentiation in response to the granulocyte macrophage colony-stimulating factor (GM-CSF). Thus, there seems to be an association between AML1-MTG16-induced myeloid maturation block and epigenetic changes of a myeloid master gene.
Rossetti
Stefano
S
Department of Cancer Genetics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
Van Unen
Leontine
L
Touw
Ivo P
IP
Hoogeveen
André T
AT
Sacchi
Nicoletta
N
D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D050676:Core Binding Factor Alpha 2 Subunit; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology; D042381:Granulocyte Precursor Cells / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000096:biosynthesis* / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection
C112643:AML1-MTG16 protein, human; D050676:Core Binding Factor Alpha 2 Subunit; D006657:Histones; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor