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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月13日

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  • 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

摘要

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.