肿瘤细胞增殖需要利用大量的能量，可导致三羧酸循环紊乱，三羧酸循环紊乱是肿瘤增殖旺盛的特性之一，和许多肿瘤发生与预后相关。原发性骨髓纤维化（PMF）是骨髓增殖性疾病的一种，目前尚无有效防治其发生、发展的方法。PMF患者伴有JAK2V617F、CALR、MPL等基因突变，部分伴有IDH1/2突变，后者是三羧酸循环中的关键基因，该基因突变导致2-HG产生增多，加剧表观遗传学紊乱，可能是促使PMF向急性髓细胞白血病（AML）转化的机制。本研究拟检测PMF及向AML转化患者的代谢组、表观遗传学变化，明确小分子代谢物及表观遗传学相关基因在PMF预后判断中的意义。构建JAK2V617F突变细胞株及小鼠模型，检测小分子代谢物及表观遗传学相关基因，并采用调节三羧酸循环的小分子物质二氯乙酸钠处理细胞株及小鼠，证实这些代谢物与PMF发生和转白的相关性，为临床预测PMF转化为白血病提供可靠的标志物。

Tumor cells requires a large amount of energy to support the rapid proliferation, which leads to three carboxylic acid cycle disorder.This metabolic disorder had been regarded as one of hallmarks of rapid turnover of tumor cells, which is associated with poor prognosis in several types of tumors. Primary myelofibrosis (PMF) is a subgroup of myeloproliferative neoplasms. Currently, there is no effective strategy to prevent the initiation and development of this disease. PMF patients have genes mutations including JAK2V617F, CALR, MPL and IDH1/2 in a small part of patients. IDH1/2 are the key genes of three carboxylic acid cycle,and these genes mutations will lead to 2-HG accumulation and in turn 2-HG promotes the conversion of PMF to acute myeloid leukemia (AML) by aberrant epigenetic regulation. We conduct this study to explore the mechanism of initiation of PMF and development to AML by analyses of metabolomics and DNA methylation patterns in PMF patients, and therefore identify the prognostic significance of metabolic markers. In order to confirm the significance of small metabolites on initiation of PMF and development to leukemia, we treat JAK2V617F induced cell lines and mice model with sodium chloroacetate to regulate the abnormality of three carboxylic acid cycle, and perform metabolomics and epigenetic profiling analyses. This study will provide reliable biomarkers and treatment targets to predict the development of leukemia from PMF.