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

Oncogene volume 29, pages 5019–5031 (2010)Cite this article

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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.

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Acknowledgements

We gratefully acknowledge Amandine Bataille, Amandine Chlemaire and Franck Ménétrier for immunocytofluorescence assays; André Bouchot for epifluorescence microscopy; and Christine Arnould for confocal analysis (SERCOBIO, Université de Bourgogne), and the Etablissement Français du Sang (EFS) of Bourgogne Franche-Comté, which kindly supplied the cord blood buffy coats. We also thank Mustapha Oulad-Abdelghani for producing the anti-MOZ antibody. We thank Robert Slany, Issai Kitabayashi, Paul Shore, Michael Cleary and Edward Chan for providing plasmids. We appreciate the fine work performed by Magali Belt in correction of English text. This work was supported by funds from the Fondation de France (Leukemia Committee to LD), the Ligue contre le Cancer (Côte d’Or committee to LD), the Ligue contre le Cancer (Rhône committee to LD), the Conseil Régional de Bourgogne (FABER to LD), the Faculty of Medicine (to J-NB) in Dijon, the National Institute of Cancer (to ES), the Ligue Nationale contre le Cancer (Label to ES), the Agence Nationale de la Recherche of France (to ES and LD) and the Canadian Cancer Society (to XJY). JP was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche of France and the Association pour la Recherche sur le Cancer (ARC). AL was supported by fellowships from the Inserm and the Région Bourgogne. RA and AJ were supported by fellowships from the Ligue contre le Cancer, Saône-et-Loire committee and national committee, respectively. BL was supported by fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche of France.

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  1. J Paggetti

    Present address: 6Current address: Laboratory of Experimental Hemato-Oncology Public Research Center for Health (CRP-Santé), Luxembourg, Luxembourg.,

  2. J Paggetti and A Largeot: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm UMR 866, Faculty of Medicine, University of Burgundy, Dijon, France

    J Paggetti, A Largeot, R Aucagne, A Jacquel, B Lagrange, J-N Bastie & L Delva

  2. Department of Medicine, McGill University Health Centre, Montréal, Québec, Canada

    X-J Yang

  3. Inserm UMR 1009, Institut Gustave Roussy, Villejuif, France

    E Solary

  4. Clinical Hematology Department, University Hospital (CHU), Dijon, France

    J-N Bastie

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Paggetti, J., Largeot, A., Aucagne, R. et al. Crosstalk between leukemia-associated proteins MOZ and MLL regulates HOX gene expression in human cord blood CD34+ cells. Oncogene 29, 5019–5031 (2010). https://doi.org/10.1038/onc.2010.254

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