HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms Journal Article


Authors: Yue, L.; Sharma, V.; Horvat, N. P.; Akuffo, A. A.; Beatty, M. S.; Murdun, C.; Colin, C.; Billington, J. M. R.; Goodheart, W. E.; Sahakian, E.; Zhang, L.; Powers, J. J.; Amin, N. E.; Lambert-Showers, Q. T.; Darville, L. N.; Pinilla-Ibarz, J.; Reuther, G. W.; Wright, K. L.; Conti, C.; Lee, J. Y.; Zheng, X.; Ng, P. Y.; Martin, M. W.; Marshall, C. G.; Koomen, J. M.; Levine, R. L.; Verma, A.; Grimes, H. L.; Sotomayor, E. M.; Shao, Z.; Epling-Burnette, P. K.
Article Title: HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms
Abstract: Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2- driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11 is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors ofHDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN. © 2020 American Society of Hematology. All rights reserved.
Journal Title: Blood
Volume: 135
Issue: 3
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2020-01-16
Start Page: 191
End Page: 207
Language: English
DOI: 10.1182/blood.2019895326
PUBMED: 31750881
PROVIDER: scopus
PMCID: PMC6966930
DOI/URL:
Notes: Article -- Export Date: 2 March 2020 -- Source: Scopus
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  1. Ross Levine
    530 Levine