Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells.

Abstract:

: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.

journal_name

Oncogene

journal_title

Oncogene

authors

Paggetti J,Largeot A,Aucagne R,Jacquel A,Lagrange B,Yang XJ,Solary E,Bastie JN,Delva L

doi

10.1038/onc.2010.254

subject

Has Abstract

pub_date

2010-09-09 00:00:00

pages

5019-31

issue

36

eissn

0950-9232

issn

1476-5594

pii

onc2010254

journal_volume

29

pub_type

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