Hydroxy-wybutosine tRNA modifications as indicators of disease progression and therapeutic targets in leukaemia.

IF 5.1 2区医学 Q1 HEMATOLOGY

British Journal of Haematology Pub Date : 2024-11-10 DOI:10.1111/bjh.19873

Xu Chen, Rui-Ze Gong, Liu-Ying Mo, Ya-Ting Cheng, Yu Ma, Yi-Tao Qi, Tong-Meng Yan, Zhi-Hong Jiang

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Abstract

Therapeutic approaches for acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) differ due to distinct diagnostic criteria and treatment strengths. However, reliable biomarkers to differentiate AML from MDS are needed. This study investigated transfer RNA (tRNA) modifications, particularly hydroxy-wybutosine (OHyW), in the transition from MDS to AML. We found a significant decrease in OHyW and its biosynthetic enzyme leucine carboxyl methyltransferase 2 (LCMT2, alias symbol is TYW4) levels in AML compared to MDS. Mass spectrometric analysis revealed distinct tRNA modification patterns, with AML showing decreased OHyW and increased precursor levels, indicating a disrupted biosynthetic pathway. Lower LCMT2 expression correlated with reduced drug sensitivity and limited differentiation potential in AML cell lines. The results highlight the pivotal role of tRNA modifications in the progression from MDS to AML and suggest that targeting LCMT2 may enhance therapeutic outcomes in AML. By understanding these molecular mechanisms, we can develop new diagnostic markers and therapeutic strategies, potentially transforming the clinical management of AML and improving patient outcomes.

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羟基-胞嘧啶 tRNA 修饰作为白血病病情发展的指标和治疗目标。

急性髓性白血病（AML）和骨髓增生异常综合征（MDS）的诊断标准和治疗强度不同，治疗方法也不尽相同。然而，区分急性髓性白血病和骨髓增生异常综合征需要可靠的生物标志物。本研究调查了转运核糖核酸（tRNA）修饰，尤其是羟基丁氨酸（OHyW），在从 MDS 向 AML 过渡的过程中的作用。我们发现，与 MDS 相比，AML 中 OHyW 及其生物合成酶亮氨酸羧基甲基转移酶 2（LCMT2，别名 TYW4）的水平明显下降。质谱分析显示了不同的 tRNA 修饰模式，AML 的 OHyW 水平降低，前体水平升高，表明生物合成途径中断。LCMT2 表达较低与 AML 细胞系药物敏感性降低和分化潜力受限有关。这些结果突显了 tRNA 修饰在从 MDS 向 AML 发展过程中的关键作用，并表明以 LCMT2 为靶点可能会提高 AML 的治疗效果。通过了解这些分子机制，我们可以开发出新的诊断标志物和治疗策略，从而有可能改变急性髓细胞性白血病的临床管理并改善患者的预后。

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来源期刊

British Journal of Haematology 医学-血液学

CiteScore

8.60

自引率

4.60%

发文量

565

审稿时长

1 months

期刊介绍： The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.