The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are associated with clonal myelopoiesis, elevated risk of death due to thrombotic complications, and transformation to acute myeloid leukemia (AML). JAK2 inhibitors improve the quality of life for MPN patients, but these approved therapeutics do not readily reduce the natural course of disease or antagonize the neoplastic clone. An understanding of the molecular and cellular changes requisite for MPN development and progression are needed to develop improved therapies. Recently, murine MPN models were demonstrated to exhibit metabolic vulnerabilities due to a high dependence on glucose. Neoplastic hematopoietic progenitor cells in these mice express elevated levels of glycolytic enzymes and exhibit enhanced levels of glycolysis and oxidative phosphorylation, and the disease phenotype of these MPN model mice is antagonized by glycolytic inhibition. While all MPN-driving mutations lead to aberrant JAK2 activation, these mutations often co-exist with mutations in genes that encode epigenetic regulators, including loss of function mutations known to enhance MPN progression. In this perspective we discuss how altered activity of epigenetic regulators (e.g., methylation and acetylation) in MPN-driving stem and progenitor cells may alter cellular metabolism and contribute to the MPN phenotype and progression of disease. Specific metabolic changes associated with epigenetic deregulation may identify patient populations that exhibit specific metabolic vulnerabilities that are absent in normal hematopoietic cells, and thus provide a potential basis for the development of more effective personalized therapeutic approaches.

Janus激酶2（JAK2）驱动的骨髓增生性肿瘤（MPN）与克隆性骨髓生成，由于血栓性并发症导致的死亡风险增加以及转化为急性髓细胞性白血病（AML）有关。JAK2抑制剂可改善MPN患者的生活质量，但这些批准的疗法不能轻易降低疾病的自然病程或拮抗肿瘤克隆。需要了解MPN发育和发展所需的分子和细胞变化，以开发改良的疗法。最近，由于对葡萄糖的高度依赖性，鼠MPN模型被证明表现出代谢脆弱性。这些小鼠中的肿瘤造血祖细胞表达的糖酵解酶水平升高，糖酵解和氧化磷酸化水平升高，这些MPN模型小鼠的疾病表型被糖酵解抑制作用所拮抗。尽管所有驱动MPN的突变均导致异常的JAK2激活，但这些突变通常与编码表观遗传调控因子的基因中的突变共存，包括已知增强MPN进展的功能性突变。从这个角度出发，我们讨论了MPN驱动干细胞和祖细胞中表观遗传调节剂的活性改变（例如，甲基化和乙酰化）如何改变细胞代谢并促进MPN表型和疾病进展。与表观遗传失调相关的特定代谢变化可能会鉴定出表现出正常造血细胞所不具有的特定代谢脆弱性的患者人群，