2. Academic Validation
  3. HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms

HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms

  • Blood. 2020 Jan 16;135(3):191-207. doi: 10.1182/blood.2019895326.
Lanzhu Yue 1 2,  Vasundhara Sharma 2,  Nathan P Horvat 2,  Afua A Akuffo 2 3,  Matthew S Beatty 2,  Cem Murdun 2 4,  Christelle Colin 2,  Julia M R Billington 2 3,  William E Goodheart 2,  Eva Sahakian 2,  Ling Zhang 5,  John J Powers 2,  Narmin E Amin 6,  Que T Lambert-Showers 4,  Lancia N Darville 7,  Javier Pinilla-Ibarz 2,  Gary W Reuther 6,  Kenneth L Wright 2,  Chiara Conti 8,  Jennifer Y Lee 8,  Xiaozhang Zheng 8,  Pui Yee Ng 8,  Matthew W Martin 8,  C Gary Marshall 8,  John M Koomen 6,  Ross L Levine 9,  Amit Verma 10,  H Leighton Grimes 11,  Eduardo M Sotomayor 12,  Zonghong Shao 1,  Pearlie K Epling-Burnette 2 13
Affiliations

Affiliations

  • 1 Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
  • 3 Cancer Biology PhD Program, University of South Florida, Tampa, FL.
  • 4 Tissue Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
  • 5 Department of Pathology, University of South Florida College of Medicine and Moffitt Cancer Center, Tampa, FL.
  • 6 Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
  • 7 Proteomics Core, Moffitt Cancer Center, Tampa, FL.
  • 8 Forma Therapeutics, Watertown, MA.
  • 9 Leukemia Center, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 10 Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY.
  • 11 Division of Experimental Hematology and Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
  • 12 Department of Hematology & Oncology, George Washington Cancer Center, Washington, DC; and.
  • 13 James A. Haley VA Hospital, Tampa, FL.
PMID: 31750881 DOI: 10.1182/blood.2019895326
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 Hdac11is 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 of HDAC11 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.

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