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

Unnikrishnan, A; Papaemmanuil, E; Beck, D; Deshpande, NP; Verma, A; Kumari, A; Woll, PS; Richards, LA; Knezevic, K; Chandrakanthan, V; Thoms, JAI; Tursky, ML; Huang, Y; Ali, Z; Olivier, J; Galbraith, S; Kulasekararaj, AG; Tobiasson, M; Karimi, M; Pellagatti, A; Wilson, SR; Lindeman, R; Young, B; Ramakrishna, R; Arthur, C; Stark, R; Crispin, P; Curnow, J; Warburton, P; Roncolato, F; Boultwood, J; Lynch, K; Jacobsen, SEW; Mufti, GJ; Hellstrom-Lindberg, E; Wilkins, MR; MacKenzie, KL; Wong, JWH; Campbell, PJ; Pimanda, JE

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

Unnikrishnan, A Papaemmanuil, E Beck, D Deshpande, NP Verma, A

Kumari, A Woll, PS Richards, LA Knezevic, K Chandrakanthan, V Thoms, JAI Tursky, ML Huang, Y

Ali, Z Olivier, J Galbraith, S Kulasekararaj, AG Tobiasson, M Karimi, M Pellagatti, A Wilson, SR Lindeman, R Young, B Ramakrishna, R Arthur, C Stark, R Crispin, P Curnow, J Warburton, P Roncolato, F Boultwood, J Lynch, K Jacobsen, SEW Mufti, GJ Hellstrom-Lindberg, E Wilkins, MR MacKenzie, KL Wong, JWH Campbell, PJ Pimanda, JE

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Publication Type:: Journal Article
Citation:: Cell Reports, 2017, 20 (3), pp. 572 - 585
Issue Date:: 2017-07-18

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Field	Value	Language
dc.contributor.author	Unnikrishnan, A	en_US
dc.contributor.author	Papaemmanuil, E	en_US
dc.contributor.author	Beck, D	en_US
dc.contributor.author	Deshpande, NP	en_US
dc.contributor.author	Verma, A https://orcid.org/0000-0003-0119-9915	en_US
dc.contributor.author	Kumari, A	en_US
dc.contributor.author	Woll, PS	en_US
dc.contributor.author	Richards, LA	en_US
dc.contributor.author	Knezevic, K	en_US
dc.contributor.author	Chandrakanthan, V	en_US
dc.contributor.author	Thoms, JAI	en_US
dc.contributor.author	Tursky, ML	en_US
dc.contributor.author	Huang, Y https://orcid.org/0000-0002-7003-3110	en_US
dc.contributor.author	Ali, Z	en_US
dc.contributor.author	Olivier, J	en_US
dc.contributor.author	Galbraith, S	en_US
dc.contributor.author	Kulasekararaj, AG	en_US
dc.contributor.author	Tobiasson, M	en_US
dc.contributor.author	Karimi, M	en_US
dc.contributor.author	Pellagatti, A	en_US
dc.contributor.author	Wilson, SR	en_US
dc.contributor.author	Lindeman, R	en_US
dc.contributor.author	Young, B	en_US
dc.contributor.author	Ramakrishna, R	en_US
dc.contributor.author	Arthur, C	en_US
dc.contributor.author	Stark, R	en_US
dc.contributor.author	Crispin, P	en_US
dc.contributor.author	Curnow, J	en_US
dc.contributor.author	Warburton, P	en_US
dc.contributor.author	Roncolato, F	en_US
dc.contributor.author	Boultwood, J	en_US
dc.contributor.author	Lynch, K	en_US
dc.contributor.author	Jacobsen, SEW	en_US
dc.contributor.author	Mufti, GJ	en_US
dc.contributor.author	Hellstrom-Lindberg, E	en_US
dc.contributor.author	Wilkins, MR	en_US
dc.contributor.author	MacKenzie, KL	en_US
dc.contributor.author	Wong, JWH	en_US
dc.contributor.author	Campbell, PJ	en_US
dc.contributor.author	Pimanda, JE	en_US
dc.date.available	2017-06-22	en_US
dc.date.issued	2017-07-18	en_US
dc.identifier.citation	Cell Reports, 2017, 20 (3), pp. 572 - 585	en_US
dc.identifier.uri	http://hdl.handle.net/10453/124973
dc.description.abstract	© 2017 The Author(s) 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.	en_US
dc.relation.ispartof	Cell Reports	en_US
dc.relation.isbasedon	10.1016/j.celrep.2017.06.067	en_US
dc.rights	info:eu-repo/semantics/openAccess
dc.subject.mesh	Humans	en_US
dc.subject.mesh	Myelodysplastic Syndromes	en_US
dc.subject.mesh	Azacitidine	en_US
dc.subject.mesh	Integrin alpha Chains	en_US
dc.subject.mesh	Genomics	en_US
dc.subject.mesh	Drug Resistance	en_US
dc.subject.mesh	Aged	en_US
dc.subject.mesh	Aged, 80 and over	en_US
dc.subject.mesh	Middle Aged	en_US
dc.subject.mesh	Female	en_US
dc.title	Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes	en_US
dc.type	Journal Article
utslib.citation.volume	3	en_US
utslib.citation.volume	20	en_US
utslib.for	1108 Medical Microbiology	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
utslib.for	1116 Medical Physiology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology
pubs.organisational-group	/University of Technology Sydney/Faculty of Engineering and Information Technology/School of Biomedical Engineering
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Strength - AAI - Advanced Analytics Institute Research Centre
pubs.organisational-group	/University of Technology Sydney/Strength - C3 - Climate Change Cluster
pubs.organisational-group	/University of Technology Sydney/Strength - CHT - Health Technologies
utslib.copyright.status	open_access	*
pubs.issue	3	en_US
pubs.publication-status	Published	en_US
pubs.volume	20	en_US

Abstract:

© 2017 The Author(s) 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.

Please use this identifier to cite or link to this item:

http://hdl.handle.net/10453/124973