Cell Reports (Jul 2017)
Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes
- 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. Kulasekararaj,
- 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. Jacobsen,
- Ghulam J. Mufti,
- Eva Hellstrom-Lindberg,
- Marc R. Wilkins,
- Karen L. MacKenzie,
- Jason W.H. Wong,
- Peter J. Campbell,
- John E. Pimanda
Affiliations
- Ashwin Unnikrishnan
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Elli Papaemmanuil
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SA, UK
- Dominik Beck
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Nandan P. Deshpande
- Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia
- Arjun Verma
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Ashu Kumari
- Children’s Cancer Institute Australia, Sydney, NSW 2052, Australia
- Petter S. Woll
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Laura A. Richards
- Children’s Cancer Institute Australia, Sydney, NSW 2052, Australia
- Kathy Knezevic
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Vashe Chandrakanthan
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Julie A.I. Thoms
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Melinda L. Tursky
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Yizhou Huang
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Zara Ali
- Children’s Cancer Institute Australia, Sydney, NSW 2052, Australia
- Jake Olivier
- School of Mathematics and Statistics, UNSW, Sydney, NSW 2052, Australia
- Sally Galbraith
- School of Mathematics and Statistics, UNSW, Sydney, NSW 2052, Australia
- Austin G. Kulasekararaj
- Department of Haematological Medicine, King’s College London School of Medicine, London WC2R 2LS, UK
- Magnus Tobiasson
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Mohsen Karimi
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Andrea Pellagatti
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom
- Susan R. Wilson
- School of Mathematics and Statistics, UNSW, Sydney, NSW 2052, Australia
- Robert Lindeman
- Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia
- Boris Young
- Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia
- Raj Ramakrishna
- Southern Sydney Haematology, Kogarah, NSW 2217, Australia
- Christopher Arthur
- Royal North Shore Hospital, St Leonards, NSW 2065, Australia
- Richard Stark
- North Coast Cancer Institute, Port Macquarie, NSW 2444, Australia
- Philip Crispin
- Canberra Hospital, Canberra, ACT 2605, Australia
- Jennifer Curnow
- Concord Repatriation General Hospital, Concord, NSW 2139, Australia
- Pauline Warburton
- Wollongong Hospital, Wollongong, NSW 2521, Australia
- Fernando Roncolato
- St George Hospital, Kogarah, NSW 2217, Australia
- Jacqueline Boultwood
- Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom
- Kevin Lynch
- Celgene International, 2017 Boudry, Switzerland
- Sten Eirik W. Jacobsen
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Ghulam J. Mufti
- Department of Haematological Medicine, King’s College London School of Medicine, London WC2R 2LS, UK
- Eva Hellstrom-Lindberg
- Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden
- Marc R. Wilkins
- Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia
- Karen L. MacKenzie
- Children’s Cancer Institute Australia, Sydney, NSW 2052, Australia
- Jason W.H. Wong
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- Peter J. Campbell
- Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SA, UK
- John E. Pimanda
- Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia
- DOI
- https://doi.org/10.1016/j.celrep.2017.06.067
- Journal volume & issue
-
Vol. 20,
no. 3
pp. 572 – 585
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.
Keywords
- myelodysplastic syndrome
- chronic myelomocytic leukemia
- 5-Azacitidine
- cell cycle quiescence
- integrin alpha 5
- cancer genomics
- clonal evolution
