MDS患者对阿扎胞苷的临床反应与HSPCs中不同的DNA甲基化变化有关

IF 15.7 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Julie A. I. Thoms, Feng Yan, Henry R. Hampton, Sarah Davidson, Swapna Joshi, Jesslyn Saw, Chowdhury H. Sarowar, Xin Ying Lim, Andrea C. Nunez, Purvi M. Kakadia, Golam Sarower Bhuyan, Xiaoheng Zou, Mary Nguyen, Elaheh S. Ghodousi, Forrest C. Koch, Fatemeh Vafaee, I. Richard Thompson, Mohammad M. Karimi, Russell Pickford, Mark J. Raftery, Sally Hough, Griselda Buckland, Michelle Bailey, Yuvaraj Ghodke, Noorul Absar, Lachlin Vaughan, Leonardo Pasalic, Chun Y. Fong, Melita Kenealy, Devendra K. Hiwase, Rohanna I. Stoddart, Soma Mohammed, Linda Lee, Freda H. Passam, Stephen R. Larsen, Kevin J. Spring, Kristen K. Skarratt, Patricia Rebeiro, Peter Presgrave, William S. Stevenson, Silvia Ling, Campbell Tiley, Stephen J. Fuller, Fernando Roncolato, Anoop K. Enjeti, Dirk Hoenemann, Charlotte Lemech, Christopher J. Jolly, Stefan K. Bohlander, David J. Curtis, Jason W. H. Wong, Ashwin Unnikrishnan, Mark Hertzberg, Jake Olivier, Mark N. Polizzotto, John E. Pimanda
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引用次数: 0

摘要

低甲基化药物是骨髓增生异常肿瘤(MDS)的一线治疗方法,但临床反应仍然不可预测。我们进行了一项2期试验,比较注射和口服阿扎胞苷(AZA),每4周给药1周或3周,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,而反应者和无反应者之间单个核细胞的整体DNA甲基化水平相当。然而,来自应答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节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6周期(临床反应通常出现),对造血干细胞有反应的造血干细胞进一步差异低甲基化表明骨髓适应是改善造血的驱动因素。这些发现表明,HSPCs的内在基线和早期药物诱导的表观遗传差异可能是MDS患者对AZA的不同临床反应的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs

Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs

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.

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来源期刊
Nature Communications
Nature Communications Biological Science Disciplines-
CiteScore
24.90
自引率
2.40%
发文量
6928
审稿时长
3.7 months
期刊介绍: Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.
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