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HDAC11 Deficiency or Inhibition Disrupts Oncogene-Induced Stress Hematopoiesis in Myeloproliferative Neoplasms
Blood ( IF 20.3 ) Pub Date : 2020-01-16 , 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
Affiliation  

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). Using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, here we report 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. While dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric BM 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 MPN patients. While 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 work establishes HDAC11 as a unique type of target molecule having therapeutic potential in MPN.

中文翻译:

HDAC11 缺乏或抑制会破坏骨髓增殖性肿瘤中致癌基因诱导的应激造血

蛋白质乙酰化是癌症发生的重要因素。组蛋白去乙酰化酶 6 (HDAC6) 控制 JAK2 翻译和蛋白质稳定性,并与 JAK2 驱动的疾病有关,最典型的例子是骨髓增生性肿瘤 (MPN)。使用新型的高选择性 HDAC 抑制剂和基因缺陷小鼠模型,我们报告说 HDAC11 而不是 HDAC6 对于致癌 JAK2 驱动的 MPN 细胞和患者样本的增殖和存活是必要的。值得注意的是,HDAC11 在原始干细胞中表达不同,并且主要根据谱系定型表达。虽然对于基于嵌合 BM 重建的正常稳态造血干细胞和祖细胞分化是不必要的,但 Hdac11 缺乏显着减少了异常巨核细胞群,改善了脾脏结构,MPLW515L-MPN 小鼠模型在初次和二次移植期间减少纤维化并增加存活率。因此,HDAC11 抑制剂是治疗 MPN 患者的一种有吸引力的疗法。虽然 JAK2 抑制剂治疗为 MPN 患者提供了实质性的临床益处,但需要确定替代治疗靶点来逆转 MPN 发病机制和控制恶性造血。这项工作将 HDAC11 确立为一种在 MPN 中具有治疗潜力的独特类型的靶分子。需要确定替代治疗靶点来逆转 MPN 发病机制和控制恶性造血。这项工作将 HDAC11 确立为一种在 MPN 中具有治疗潜力的独特类型的靶分子。需要确定替代治疗靶点来逆转 MPN 发病机制和控制恶性造血。这项工作将 HDAC11 确立为一种在 MPN 中具有治疗潜力的独特类型的靶分子。
更新日期:2020-01-16
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