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

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 () and John E. Pimanda ()
Additional contact information
Julie A. I. Thoms: University of New South Wales
Feng Yan: Walter and Eliza Hall Institute of Medical Research
Henry R. Hampton: University of New South Wales
Sarah Davidson: John Curtin School of Medical Research
Swapna Joshi: University of New South Wales
Jesslyn Saw: Monash University
Chowdhury H. Sarowar: University of New South Wales
Xin Ying Lim: University of New South Wales
Andrea C. Nunez: University of New South Wales
Purvi M. Kakadia: The University of Auckland
Golam Sarower Bhuyan: University of New South Wales
Xiaoheng Zou: University of New South Wales
Mary Nguyen: University of New South Wales
Elaheh S. Ghodousi: University of New South Wales
Forrest C. Koch: University of New South Wales
Fatemeh Vafaee: University of New South Wales
I. Richard Thompson: King’s College London
Mohammad M. Karimi: King’s College London
Russell Pickford: University of New South Wales
Mark J. Raftery: University of New South Wales
Sally Hough: University of New South Wales
Griselda Buckland: John Curtin School of Medical Research
Michelle Bailey: University of New South Wales
Yuvaraj Ghodke: John Curtin School of Medical Research
Noorul Absar: University of New South Wales
Lachlin Vaughan: University of New South Wales
Leonardo Pasalic: Westmead Hospital
Chun Y. Fong: Austin Health
Melita Kenealy: Cabrini Hospital
Devendra K. Hiwase: Royal Adelaide Hospital
Rohanna I. Stoddart: University of New South Wales
Soma Mohammed: Westmead Hospital
Linda Lee: Royal North Shore Hospital
Freda H. Passam: Heart Research Institute
Stephen R. Larsen: Royal Prince Alfred Hospital
Kevin J. Spring: Western Sydney University and Ingham Institute for Applied Medical Research
Kristen K. Skarratt: Nepean Hospital
Patricia Rebeiro: Blacktown Hospital
Peter Presgrave: Wollongong Hospital
William S. Stevenson: Royal North Shore Hospital
Silvia Ling: Liverpool Hospital
Campbell Tiley: Gosford Hospital
Stephen J. Fuller: Nepean Hospital
Fernando Roncolato: St. George Hospital
Anoop K. Enjeti: Calvary Mater Hospital
Dirk Hoenemann: Otway Pharmaceutical Development and Consulting Pty Ltd
Charlotte Lemech: Prince of Wales Hospital
Christopher J. Jolly: University of New South Wales
Stefan K. Bohlander: The University of Auckland
David J. Curtis: Monash University
Jason W. H. Wong: The University of Hong Kong
Ashwin Unnikrishnan: University of New South Wales
Mark Hertzberg: Prince of Wales Hospital
Jake Olivier: University of New South Wales
Mark N. Polizzotto: John Curtin School of Medical Research
John E. Pimanda: University of New South Wales

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-59796-x

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