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
{"title":"MDS患者对阿扎胞苷的临床反应与HSPCs中不同的DNA甲基化变化有关","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, 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","doi":"10.1038/s41467-025-59796-x","DOIUrl":null,"url":null,"abstract":"<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>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"11 1","pages":"4451"},"PeriodicalIF":15.7000,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs\",\"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, 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\",\"doi\":\"10.1038/s41467-025-59796-x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<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>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"11 1\",\"pages\":\"4451\"},\"PeriodicalIF\":15.7000,\"publicationDate\":\"2025-05-13\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-025-59796-x\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-025-59796-x","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs
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.
期刊介绍:
Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.