Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cellsin vivo
Author:
Thoms Julie A.I.ORCID, Yan FengORCID, Hampton Henry R.ORCID, 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, 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.ORCID, Bohlander Stefan K.ORCID, Curtis David J.ORCID, Wong Jason W HORCID, Unnikrishnan Ashwin, Hertzberg Mark, Olivier JakeORCID, Polizzotto Mark N.ORCID, Pimanda John E.ORCID
Abstract
AbstractHypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated within vivodynamics of DNA hypomethylation, we conducted a phase 2 trial for MDS using both injection and oral azacitidine (AZA). We established that global DNA methylation levels in peripheral blood and bone marrow mononuclear cells were comparable in AZA responders and non-responders during their course of treatment. However, there were distinct baseline and early drug induced differences in CpG methylation in haematopoietic stem and progenitor cells (HSPCs) in responders compared to non-responders that overlapped with regulatory regions of genes associated with tissue patterning, cell migration and myeloid differentiation. Following six cycles of therapy when clinical response typically manifests, differential hypomethylation in responder HSPCs pointed to marrow adaptation as a driver of enhanced haematopoiesis. Taken together, CpG methylation differences in HSPCs may explain variable response to AZA.
Publisher
Cold Spring Harbor Laboratory
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