HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms

Lanzhu Yue, Vasundhara Sharma, Nathan P. Horvat, Afua A. Akuffo, Matthew S. Beatty, Cem Murdun, Christelle Colin, Julia M.R. Billington, William E. Goodheart, Eva Sahakian, Ling Zhang, John J. Powers, Narmin E. Amin, Que T. Lambert-Showers, Lancia N. Darville, Javier Pinilla-Ibarz, Gary W. Reuther, Kenneth L. Wright, Chiara Conti, Jennifer Y. LeeXiaozhang Zheng, Pui Yee Ng, Matthew W. Martin, C. Gary Marshall, John M. Koomen, Ross L. Levine, Amit Verma, H. Leighton Grimes, Eduardo M. Sotomayor, Zonghong Shao, Pearlie K. Epling-Burnette

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)191-207
Number of pages17
JournalBlood
Volume135
Issue number3
DOIs
StatePublished - Jan 16 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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