Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

• DOI: 10.1016/j.celrep.2017.06.067
• Publication Date: 2017-07-18T22:47:19Z
• Authors: Ashwin Unnikrishnan; Elli Papaemmanuil; Dominik Beck; Nandan P. Deshpande; Arjun Verma; Ashu Kumari; Petter S. Woll; Laura A. Richards; Kathy Knezevic; Vashe Chandrakanthan; Julie A.I. Thoms; Melinda L. Tursky; Yizhou Huang; Zara Ali; Jake Olivier; Sally Galbraith; Austin G. Kulasek...; Magnus Tobiasson; Mohsen Karimi; Andrea Pellagatti; Susan R. Wilson; Robert Lindeman; Boris Young; Raj Ramakrishna; Christopher Arthur; Richard Stark; Philip Crispin; Jennifer Curnow; Pauline Warburton; Fernando Roncolato; Jacqueline Boultwood; Kevin Lynch; Sten Eirik W. Jac...; Ghulam J. Mufti; Eva Hellstrom-Lin...; Marc R. Wilkins; Karen L. MacKenzie; Jason W.H. Wong; Peter J. Campbell; John E. Pimanda
• Keywords: Azacitidine; Chronic myelomonocytic leukemia

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response manifests after many months treatment transient. reasons underlying AZA resistance unknown, few alternatives exist for non-responders. Here, we show responders have more hematopoietic progenitor cells (HPCs) in cell cycle. Non-responder HPC quiescence mediated integrin α5 (ITGA5) signaling their potential improved combining with an ITGA5 inhibitor. associated induction inflammatory HPCs vivo. By molecular bar coding tracking individual clones, found that, although alters sub-clonal contribution to different lineages, founder clones not eliminated continue drive even complete responders.