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

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 PellagattiSusan 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

King's College London

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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.

Original language	English
Pages (from-to)	572-585
Number of pages	14
Journal	Cell Reports
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2017.06.067
Publication status	Published - 18 Jul 2017

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Unnikrishnan, A., Papaemmanuil, E., Beck, D., Deshpande, N. P., Verma, A., Kumari, A., Woll, P. S., Richards, L. A., Knezevic, K., Chandrakanthan, V., Thoms, J. A. I., Tursky, M. L., Huang, Y., Ali, Z., Olivier, J., Galbraith, S., Kulasekararaj, A. G., Tobiasson, M., Karimi, M., ... Pimanda, J. E. (2017). Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes. Cell Reports, 20(3), 572-585. https://doi.org/10.1016/j.celrep.2017.06.067

@article{d615861d33cf47d1a688438acc68465a,

title = "Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes",

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",

author = "Ashwin Unnikrishnan and Elli Papaemmanuil and Dominik Beck and Deshpande, {Nandan P.} and Arjun Verma and Ashu Kumari and Woll, {Petter S.} and Richards, {Laura A.} and Kathy Knezevic and Vashe Chandrakanthan and Thoms, {Julie A.I.} and Tursky, {Melinda L.} and Yizhou Huang and Zara Ali and Jake Olivier and Sally Galbraith and Kulasekararaj, {Austin G.} and Magnus Tobiasson and Mohsen Karimi and Andrea Pellagatti and Wilson, {Susan R.} and Robert Lindeman and Boris Young and Raj Ramakrishna and Christopher Arthur and Richard Stark and Philip Crispin and Jennifer Curnow and Pauline Warburton and Fernando Roncolato and Jacqueline Boultwood and Kevin Lynch and Jacobsen, {Sten Eirik W.} and Mufti, {Ghulam J.} and Eva Hellstrom-Lindberg and Wilkins, {Marc R.} and MacKenzie, {Karen L.} and Wong, {Jason W.H.} and Campbell, {Peter J.} and Pimanda, {John E.}",

year = "2017",

month = jul,

day = "18",

doi = "10.1016/j.celrep.2017.06.067",

language = "English",

volume = "20",

pages = "572--585",

journal = "Cell Reports",

issn = "2211-1247",

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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 2017, 'Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes', Cell Reports, vol. 20, no. 3, pp. 572-585. https://doi.org/10.1016/j.celrep.2017.06.067

TY - JOUR

T1 - Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes

AU - Unnikrishnan, Ashwin

AU - Papaemmanuil, Elli

AU - Beck, Dominik

AU - Deshpande, Nandan P.

AU - Verma, Arjun

AU - Kumari, Ashu

AU - Woll, Petter S.

AU - Richards, Laura A.

AU - Knezevic, Kathy

AU - Chandrakanthan, Vashe

AU - Thoms, Julie A.I.

AU - Tursky, Melinda L.

AU - Huang, Yizhou

AU - Ali, Zara

AU - Olivier, Jake

AU - Galbraith, Sally

AU - Kulasekararaj, Austin G.

AU - Tobiasson, Magnus

AU - Karimi, Mohsen

AU - Pellagatti, Andrea

AU - Wilson, Susan R.

AU - Lindeman, Robert

AU - Young, Boris

AU - Ramakrishna, Raj

AU - Arthur, Christopher

AU - Stark, Richard

AU - Crispin, Philip

AU - Curnow, Jennifer

AU - Warburton, Pauline

AU - Roncolato, Fernando

AU - Boultwood, Jacqueline

AU - Lynch, Kevin

AU - Jacobsen, Sten Eirik W.

AU - Mufti, Ghulam J.

AU - Hellstrom-Lindberg, Eva

AU - Wilkins, Marc R.

AU - MacKenzie, Karen L.

AU - Wong, Jason W.H.

AU - Campbell, Peter J.

AU - Pimanda, John E.

PY - 2017/7/18

Y1 - 2017/7/18

N2 - 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.

AB - 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.

KW - myelodysplastic syndrome

KW - chronic myelomocytic leukemia

KW - 5-Azacitidine

KW - cell cycle quiescence

KW - integrin alpha 5

KW - cancer genomics

KW - clonal evolution

U2 - 10.1016/j.celrep.2017.06.067

DO - 10.1016/j.celrep.2017.06.067

M3 - Article

SN - 2211-1247

VL - 20

SP - 572

EP - 585

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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