Thoms Julie A I, Yan Feng, Hampton Henry R, Davidson Sarah, Joshi Swapna, Saw Jesslyn, Sarowar Chowdhury H, Lim Xin Ying, Nunez Andrea C, Kakadia Purvi M, Bhuyan Golam Sarower, Zou Xiaoheng, Nguyen Mary, Ghodousi Elaheh S, Koch Forrest C, Vafaee Fatemeh, Thompson I Richard, Karimi Mohammad M, Pickford Russell, Raftery Mark J, Hough Sally, Buckland Griselda, Bailey Michelle, Ghodke Yuvaraj, Absar Noorul, Vaughan Lachlin, Pasalic Leonardo, Fong Chun Y, Kenealy Melita, Hiwase Devendra K, Stoddart Rohanna I, Mohammed Soma, Lee Linda, Passam Freda H, Larsen Stephen R, Spring Kevin J, Skarratt Kristen K, Rebeiro Patricia, Presgrave Peter, Stevenson William S, Ling Silvia, Tiley Campbell, Fuller Stephen J, Roncolato Fernando, Enjeti Anoop K, Hoenemann Dirk, Lemech Charlotte, Jolly Christopher J, Bohlander Stefan K, Curtis David J, Wong Jason W H, Unnikrishnan Ashwin, Hertzberg Mark, Olivier Jake, Polizzotto Mark N, Pimanda John E
School of Biomedical Sciences, University of New South Wales, Sydney, NSW, Australia.
Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
Nat Commun. 2025 May 13;16(1):4451. doi: 10.1038/s41467-025-59796-x.
Hypomethylating agents are frontline therapies for myelodysplastic neoplasms (MDS), yet clinical responses remain unpredictable. We conducted a phase 2 trial comparing injectable and oral azacitidine (AZA) administered over one or three weeks per four-week cycle, with the primary objective of investigating whether response is linked to in vivo drug incorporation or DNA hypomethylation. Our findings show that injection results in higher drug incorporation, but lower DNA demethylation per cycle, while global DNA methylation levels in mononuclear cells are comparable between responders and non-responders. However, hematopoietic stem and progenitor cells (HSPCs) from responders exhibit distinct baseline and early treatment-induced CpG methylation changes at regulatory regions linked to tissue patterning, cell migration, and myeloid differentiation. By cycle six-when clinical responses typically emerge-further differential hypomethylation in responder HSPCs suggests marrow adaptation as a driver of improved hematopoiesis. These findings indicate that intrinsic baseline and early drug-induced epigenetic differences in HSPCs may underlie the variable clinical response to AZA in MDS.
低甲基化剂是骨髓增生异常肿瘤（MDS）的一线治疗药物，但临床反应仍然不可预测。我们进行了一项2期试验，比较每4周周期内每周一次或三周一次注射和口服阿扎胞苷（AZA），主要目的是研究反应是否与体内药物掺入或DNA低甲基化有关。我们的研究结果表明，注射导致更高的药物掺入，但每个周期的DNA去甲基化程度较低，而单核细胞中的总体DNA甲基化水平在反应者和无反应者之间相当。然而，反应者的造血干细胞和祖细胞（HSPCs）在与组织模式、细胞迁移和髓系分化相关的调控区域表现出明显的基线和早期治疗诱导的CpG甲基化变化。到第六周期时——通常此时会出现临床反应——反应者HSPCs中进一步的差异性低甲基化表明骨髓适应性是造血改善的驱动因素。这些发现表明，HSPCs中内在的基线和早期药物诱导的表观遗传差异可能是MDS患者对AZA临床反应可变的基础。
