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

doi:10.1016/j.celrep.2017.06.067

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

Cell Rep. 2017 Jul 18;20(3):572-585. doi: 10.1016/j.celrep.2017.06.067.

Authors

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

Affiliations

¹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia. Electronic address: ashwin.unnikrishnan@unsw.edu.au.
² Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SA, UK; Center for Molecular Oncology and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
³ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Centre for Health Technologies and the School of Software, University of Technology, Sydney, NSW 2007, Australia.
⁴ Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia; School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia.
⁵ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Climate Change Cluster, University of Technology, Sydney, NSW 2007, Australia.
⁶ Children's Cancer Institute Australia, Sydney, NSW 2052, Australia.
⁷ Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden; Haematopoietic Stem Cell Biology Laboratory, MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
⁸ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia.
⁹ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Children's Cancer Institute Australia, Sydney, NSW 2052, Australia; Blood, Stem Cells and Cancer Research, St Vincent's Centre for Applied Medical Research, St Vincent's Hospital, Sydney, NSW 2010, Australia.
¹⁰ School of Mathematics and Statistics, UNSW, Sydney, NSW 2052, Australia.
¹¹ Department of Haematological Medicine, King's College London School of Medicine, London WC2R 2LS, UK.
¹² Department of Medicine, Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, 141 86 Stockholm, Sweden.
¹³ Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.
¹⁴ School of Mathematics and Statistics, UNSW, Sydney, NSW 2052, Australia; Mathematical Sciences Institute, ANU, Canberra, ACT 0200, Australia.
¹⁵ Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia.
¹⁶ Southern Sydney Haematology, Kogarah, NSW 2217, Australia.
¹⁷ Royal North Shore Hospital, St Leonards, NSW 2065, Australia.
¹⁸ North Coast Cancer Institute, Port Macquarie, NSW 2444, Australia.
¹⁹ Canberra Hospital, Canberra, ACT 2605, Australia.
²⁰ Concord Repatriation General Hospital, Concord, NSW 2139, Australia.
²¹ Wollongong Hospital, Wollongong, NSW 2521, Australia.
²² St George Hospital, Kogarah, NSW 2217, Australia.
²³ Celgene International, 2017 Boudry, Switzerland.
²⁴ Systems Biology Initiative, School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia; School of Biotechnology and Biomolecular Sciences, UNSW, Sydney, NSW 2052, Australia; Ramaciotti Centre for Gene Function Analysis, UNSW, Sydney, NSW 2052, Australia.
²⁵ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Saffron Walden CB10 1SA, UK. Electronic address: pc8@sanger.ac.uk.
²⁶ Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Electronic address: jpimanda@unsw.edu.au.

PMID: 28723562
DOI: 10.1016/j.celrep.2017.06.067

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: 5-Azacitidine; cancer genomics; cell cycle quiescence; chronic myelomocytic leukemia; clonal evolution; integrin alpha 5; myelodysplastic syndrome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Aged, 80 and over
Azacitidine / administration & dosage*
Drug Resistance* / drug effects
Drug Resistance* / genetics
Female
Genomics*
Humans
Integrin alpha Chains / genetics
Integrin alpha Chains / metabolism
Middle Aged
Myelodysplastic Syndromes* / drug therapy
Myelodysplastic Syndromes* / genetics
Myelodysplastic Syndromes* / metabolism

Substances

Integrin alpha Chains
Azacitidine

Abstract

Publication types

MeSH terms

Substances

Grants and funding