Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs
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.
Article Details
Authors (56)
Julie A. I. Thoms
Feng Yan
Materials Science and Engineering Program, School for Engineering of Matter, Transport and Energy
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
Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre
Mark J. Raftery
Sally Hough
Griselda Buckland
Michelle Bailey
Yuvaraj Ghodke
Noorul Absar
Lachlin Vaughan
Leonardo Pasalic
Chun Y. Fong
Melita Kenealy
Cabrini Hospital, Malvern, VIC, Australia
Devendra K. Hiwase
Rohanna I. Stoddart
Soma Mohammed
Linda Lee
Freda H. Passam
Haematology Research Group, Charles Perkins Centre
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
Clinical Haematology, Alfred Health, Melbourne, VIC, Australia
Jason W. H. Wong
Ashwin Unnikrishnan
Mark Hertzberg
Jake Olivier
Mark N. Polizzotto
John E. Pimanda