HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms
| Autor: | Ross L. Levine, Chiara Conti, Lanzhu Yue, Eva Sahakian, Nathan P. Horvat, Amit Verma, John Powers, Narmin E. Amin, Afua A. Akuffo, Kenneth L. Wright, C. Gary Marshall, Pui Yee Ng, Ling Zhang, Javier Pinilla-Ibarz, Xiaozhang Zheng, John M. Koomen, Julia M.R. Billington, Zonghong Shao, Matthew Beatty, Lancia Darville, Christelle M. Colin, Pearlie K. Epling-Burnette, Eduardo M. Sotomayor, Que T. Lambert-Showers, Jennifer Y. Lee, Matthew W. Martin, Gary W. Reuther, Cem Murdun, H. Leighton Grimes, William E. Goodheart, Vasundhara Sharma |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Immunology
Population Apoptosis Biology Biochemistry Histone Deacetylases Mice medicine Tumor Cells Cultured Animals Humans Progenitor cell education Cell Proliferation Mice Knockout education.field_of_study Myeloproliferative Disorders Myeloid Neoplasia HDAC11 Cell Cycle food and beverages Cell Biology Hematology Janus Kinase 1 Oncogenes Hematopoiesis Transplantation Histone Deacetylase Inhibitors Mice Inbred C57BL Haematopoiesis STAT Transcription Factors medicine.anatomical_structure Mutation Cancer research Histone deacetylase Bone marrow Stem cell |
| Zdroj: | Blood |
| ISSN: | 1528-0020 |
| Popis: | 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: | OpenAIRE |
| Externí odkaz: |
|