HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms.

Autor: Yue L; Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China.; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Sharma V; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Horvat NP; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Akuffo AA; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.; Cancer Biology PhD Program, University of South Florida, Tampa, FL., Beatty MS; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Murdun C; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.; Tissue Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Colin C; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Billington JMR; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.; Cancer Biology PhD Program, University of South Florida, Tampa, FL., Goodheart WE; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Sahakian E; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Zhang L; Department of Pathology, University of South Florida College of Medicine and Moffitt Cancer Center, Tampa, FL., Powers JJ; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Amin NE; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Lambert-Showers QT; Tissue Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Darville LN; Proteomics Core, Moffitt Cancer Center, Tampa, FL., Pinilla-Ibarz J; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Reuther GW; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Wright KL; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Conti C; Forma Therapeutics, Watertown, MA., Lee JY; Forma Therapeutics, Watertown, MA., Zheng X; Forma Therapeutics, Watertown, MA., Ng PY; Forma Therapeutics, Watertown, MA., Martin MW; Forma Therapeutics, Watertown, MA., Marshall CG; Forma Therapeutics, Watertown, MA., Koomen JM; Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL., Levine RL; Leukemia Center, Memorial Sloan Kettering Cancer Center, New York, NY., Verma A; Division of Hemato-Oncology, Department of Oncology, Albert Einstein College of Medicine, Bronx, NY., Grimes HL; Division of Experimental Hematology and Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH., Sotomayor EM; Department of Hematology & Oncology, George Washington Cancer Center, Washington, DC; and., Shao Z; Department of Hematology, Tianjin Medical University General Hospital, Tianjin, China., Epling-Burnette PK; Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.; James A. Haley VA Hospital, Tampa, FL.
Jazyk: angličtina
Zdroj: Blood [Blood] 2020 Jan 16; Vol. 135 (3), pp. 191-207.
DOI: 10.1182/blood.2019895326
Abstrakt: 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.
Databáze: MEDLINE