Myelodysplastic neoplasms (MDS) are clonal disorders of hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenia, and dysplasia, which often progress to acute myeloid leukemia (AML) [1]. Decitabine (DAC), a hypomethylating agents (HMAs), plays a crucial role in the treatment of MDS [2]. However, the complete remission rate with HMAs remains low at 15–20%, and nearly half of the patients ultimately develop resistance during therapy [3, 4]. The molecular mechanisms underlying resistance to decitabine in MDS are still not fully understood [5]. With an increasing understanding of tumor pathogenesis, metabolic reprogramming, especially enhanced reductive carboxylation of glutamine or disrupted oxidative phosphorylation, is also reported to be closely associated with drug resistance in hematological malignancies [6, 7].

Herein, a combination of genome-wide CRISPR/Cas9 library screening and whole exome sequencing (WES) was employed to identify candidate genes involved in decitabine sensitivity. OGDH, which encodes a key enzyme in the tricarboxylic acid (TCA) cycle, was identified as a regulator of resistance to decitabine in MDS. The biological functions of OGDH in regulating glutamine metabolism were explored both in vitro and in vivo. Overall, we first reported that low expression of OGDH enhances reductive glutamine metabolism in MDS. The results highlight the important role of OGDH in resistance to decitabine and provide insights into potential therapeutic strategies for MDS, including targeting glutaminase (GLS).

骨髓增生异常肿瘤（myelodysgrowth neoplasms， MDS）是造血干细胞的克隆性疾病，以无效造血、血细胞减少和发育不良为特征，常发展为急性髓系白血病（acute myeloid leukemia， AML）[1]。地西他滨 （DAC） 是一种低甲基化剂 （HMA），在 MDS 的治疗中起着至关重要的作用 [2]。然而，HMA 的完全缓解率仍然很低，为 15-20%，近一半的患者最终在治疗期间产生耐药 [3， 4]。MDS 对地西他滨耐药的分子机制仍未完全清楚 [5]。随着对肿瘤发病机制的了解越来越深入，代谢重编程，特别是谷氨酰胺增强的还原羧化或破坏的氧化磷酸化，也与血液系统恶性肿瘤的耐药性密切相关 [6， 7]。

在此，采用全基因组 CRISPR/Cas9 文库筛选和全外显子组测序 （WES） 的组合来鉴定参与地西他滨敏感性的候选基因。OGDH 编码三羧酸 （TCA） 循环中的关键酶，被确定为 MDS 中对地西他滨耐药的调节因子。在体外和体内探讨了 OGDH 在调节谷氨酰胺代谢中的生物学功能。总体而言，我们首先报道了 OGDH 的低表达增强了 MDS 中的还原性谷氨酰胺代谢。结果强调了 OGDH 在地西他滨耐药性中的重要作用，并为 MDS 的潜在治疗策略提供了见解，包括靶向谷氨酰胺酶 （GLS）。