Clinical Response to Azacitidine in Myelodysplastic Neoplasms is Associated with Distinct DNA Methylation Changes in Haematopoietic Stem and Progenitor cells in vivo
Thoms, J. A. I.; Yan, F.; Hampton, H. R.; Davidson, S.; Joshi, S.; Saw, J.; Sarowar, C. H.; Lim, X. Y.; Nunez, A. C.; Kakadia, P. M.; Bhuyan, G. S.; Zou, X.; Nguyen, M.; Ghodousi, E. S.; Koch, F. C.; Vafaee, F.; Pickford, R.; Raftery, M. J.; Hough, S.; Buckland, G.; Bailey, M.; Ghodke, Y.; Absar, N.; Vaughan, L.; Pasalic, L.; Fong, C. Y.; Kenealy, M.; Hiwase, D. K.; Stoddart, R. I.; Mohammed, S.; Lee, L.; Passam, F. H.; Larsen, S. R.; Spring, K. J.; Skarratt, K. K.; Rebeiro, P.; Presgrave, P.; Stevenson, W. S.; Ling, S.; Tiley, C.; Fuller, S. J.; Roncolato, F.; Enjeti, A. K.; Hoenemann, D.; Le
Show 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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