Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells.
MOZ and MLL, encoding a histone acetyltransferase (HAT) and a histone methyltransferase, respectively, are targets for recurrent chromosomal translocations found in acute myeloblastic or lymphoblastic leukemia. In MOZ (MOnocytic leukemia Zinc-finger protein)/CBP- or mixed lineage leukemia (MLL)-rearranged leukemias, abnormal levels of HOX transcription factors have been found to be critical for leukemogenesis. We show that MOZ and MLL cooperate to regulate these key genes in human cord blood CD34+ cells. These chromatin-modifying enzymes interact, colocalize and functionally cooperate, and both are recruited to multiple HOX promoters. We also found that WDR5, an adaptor protein essential for lysine 4 trimethylation of histone H3 (H3K4me3) by MLL, colocalizes and interacts with MOZ. We detected the binding of the HAT MOZ to H3K4me3, thus linking histone methylation to acetylation. In CD34+ cells, depletion of MLL causes release of MOZ from HOX promoters, which is correlated to defective histone activation marks, leading to repression of HOX gene expression and alteration of commitment of CD34+ cells into myeloid progenitors. Thus, our results unveil the role of the interaction between MOZ and MLL in CD34+ cells in which both proteins have a critical role in hematopoietic cell-fate decision, suggesting a new molecular mechanism by which MOZ or MLL deregulation leads to leukemogenesis.
Paggetti
J
J
Inserm UMR 866, Faculty of Medicine, University of Burgundy, Dijon, France.
Largeot
A
A
Aucagne
R
R
Jacquel
A
A
Lagrange
B
B
Yang
X-J
XJ
Solary
E
E
Bastie
J-N
JN
Delva
L
L
D018952:Antigens, CD34 / Q000378:metabolism*; D001773:Blood Cells / Q000378:metabolism; D002478:Cells, Cultured; D005312:Fetal Blood / Q000378:metabolism*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020014:K562 Cells; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020239:Receptor Cross-Talk / Q000502:physiology; D014018:Tissue Distribution; D020298:U937 Cells
D018952:Antigens, CD34; D006657:Histones; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; C497422:KMT2A protein, human; C502547:WDR5 protein, human; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human