| Literature DB >> 28723562 |
Ashwin Unnikrishnan1, Elli Papaemmanuil2, Dominik Beck3, Nandan P Deshpande4, Arjun Verma5, Ashu Kumari6, Petter S Woll7, Laura A Richards6, Kathy Knezevic8, Vashe Chandrakanthan8, Julie A I Thoms8, Melinda L Tursky9, Yizhou Huang3, Zara Ali6, Jake Olivier10, Sally Galbraith10, Austin G Kulasekararaj11, Magnus Tobiasson12, Mohsen Karimi12, Andrea Pellagatti13, Susan R Wilson14, Robert Lindeman15, Boris Young15, Raj Ramakrishna16, Christopher Arthur17, Richard Stark18, Philip Crispin19, Jennifer Curnow20, Pauline Warburton21, Fernando Roncolato22, Jacqueline Boultwood13, Kevin Lynch23, Sten Eirik W Jacobsen7, Ghulam J Mufti11, Eva Hellstrom-Lindberg12, Marc R Wilkins24, Karen L MacKenzie6, Jason W H Wong8, Peter J Campbell25, John E Pimanda26.
Abstract
Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and 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 only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.Entities:
Keywords: 5-Azacitidine; cancer genomics; cell cycle quiescence; chronic myelomocytic leukemia; clonal evolution; integrin alpha 5; myelodysplastic syndrome
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Year: 2017 PMID： 28723562 DOI： 10.1016/j.celrep.2017.06.067
Source DB: PubMed Journal: Cell Rep Impact factor: 9.423