Increased energy requirement and metabolic reprograming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2 driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high fat diet improved survival, while high glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2 mutant hematopoietic stem and progenitor cells that were altered in comparison with wildtype controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPN. These effects were additive with the JAK1/2 inhibitor, Ruxolitinib, in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPN and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPN.

中文翻译：

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JAK2突变造血细胞表现出代谢改变，可用于治疗骨髓增生性肿瘤


能量需求增加和代谢重编程是癌细胞的标志。我们发现造血细胞的代谢改变是突变 JAK2 驱动的骨髓增殖性肿瘤 (MPN) 发病机制的基础。我们发现突变型 JAK2 的表达增强和破坏了 MPN 细胞的代谢活性，导致体内全身代谢变化，包括低血糖、脂肪组织萎缩和早期死亡。 MPN 小鼠模型中的低血糖与红细胞生成亢进相关，是由于糖酵解升高和氧化磷酸化增加共同导致的。通过高脂肪饮食调节营养供应可提高生存率，而高葡萄糖饮食则可增强 MPN 表型。转录组学和代谢组学分析发现，JAK2 突变型造血干细胞和祖细胞中的许多代谢节点与野生型对照相比发生了改变。我们研究了 Pfkfb3（糖酵解的关键调节酶）水平升高的后果，发现用小分子 3PO 对 Pfkfb3 进行药理学抑制可逆转低血糖并减少 MPN 的造血表现。这些作用在体内和体外与 JAK1/2 抑制剂 Ruxolitinib 相加。 3PO 对糖酵解的抑制改变了氧化还原稳态，导致活性氧的积累并增加了细胞凋亡率。我们的研究结果揭示了代谢改变对 MPN 发病机制的贡献，并表明突变细胞的代谢依赖性代表了可用于治疗 MPN 的脆弱性。