Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cells in vivo
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, 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
{"title":"Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cells in vivo","authors":"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, 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","doi":"10.1101/2024.07.19.24310679","DOIUrl":null,"url":null,"abstract":"Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics 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.","PeriodicalId":501203,"journal":{"name":"medRxiv - Hematology","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Hematology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.19.24310679","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
Hypomethylating agents are used as frontline therapy for myelodysplastic neoplasms (MDS), but clinical response is unpredictable. To determine whether response was associated with in vivo dynamics 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.
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