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

被引：96

作者：

Unnikrishnan, Ashwin ^{[1
,2
]}

Papaemmanuil, Elli ^{[3
,4
]}

Beck, Dominik ^{[1
,2
,5
,6
]}

Deshpande, Nandan P. ^{[8
]}

Verma, Arjun ^{[1
,2
,9
]}

Kumari, Ashu ^{[10
]}

Woll, Petter S. ^{[11
,12
]}

Richards, Laura A. ^{[10
]}

Knezevic, Kathy ^{[1
,2
]}

Chandrakanthan, Vashe ^{[1
,2
]}

Thoms, Julie A. I. ^{[1
,2
]}

Tursky, Melinda L. ^{[1
,2
,10
,13
]}

Huang, Yizhou ^{[1
,2
,5
,6
]}

Ali, Zara

Olivier, Jake ^{[14
]}

Galbraith, Sally ^{[14
]}

Kulasekararaj, Austin G. ^{[15
]}

Tobiasson, Magnus ^{[11
]}

Karimi, Mohsen ^{[11
]}

Pellagatti, Andrea ^{[16
]}

Wilson, Susan R. ^{[14
,17
]}

Lindeman, Robert ^{[18
]}

Young, Boris ^{[18
]}

Ramakrishna, Raj ^{[19
]}

Arthur, Christopher ^{[20
]}

Stark, Richard ^{[21
]}

Crispin, Philip ^{[22
]}

Curnow, Jennifer ^{[22
,23
,28
]}

Warburton, Pauline ^{[24
]}

Roncolato, Fernando ^{[25
]}

Boultwood, Jacqueline ^{[16
]}

Lynch, Kevin ^{[26
]}

Jacobsen, Sten Eirik W. ^{[11
,12
]}

Mufti, Ghulam J. ^{[15
]}

Hellstrom-Lindberg, Eva ^{[11
]}

Wilkins, Marc R. ^{[7
,8
,27
]}

MacKenzie, Karen L. ^{[10
]}

Wong, Jason W. H. ^{[1
,2
]}

Campbell, Peter J. ^{[3
]}

Pimanda, John E. ^{[1
,2
,18
]}

机构：

[1] UNSW, Lowy Canc Res Ctr, Adult Canc Program, Sydney, NSW 2052, Australia

[2] UNSW, Prince Wales Clin Sch, Sydney, NSW 2052, Australia

[3] Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Saffron Walden CB10 1SA, Essex, England

[4] Mem Sloan Kettering Canc Ctr, Ctr Mol Oncol, New York, NY 10065 USA

[5] Univ Technol Sydney, Ctr Hlth Technol, Sydney, NSW 2007, Australia

[6] Univ Technol Sydney, Sch Software, Sydney, NSW 2007, Australia

[7] UNSW, Sch Biotechnol & Biomol Sci, Syst Biol Initiat, Sydney, NSW 2052, Australia

[8] UNSW, School Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia

[9] Univ Technol Sydney, Climate Change Cluster, Sydney, NSW 2007, Australia

[10] Childrens Canc Inst Australia, Sydney, NSW 2052, Australia

[11] Karolinska Univ, Karolinska Inst, Ctr Hematol & Regenerat Med, Dept Med,Hosp Huddinge, S-14186 Stockholm, Sweden

[12] Univ Oxford, Weatherall Inst Mol Med, MRC Mol Haematol Unit, Haematopoiet Stem Cell Biol Lab, Oxford OX3 9DS, England

[13] St Vincents Hosp, St Vincents Ctr Appl Med Res, Blood Stem Cells & Canc Res, Sydney, NSW 2010, Australia

[14] UNSW, Sch Math & Stat, Sydney, NSW 2052, Australia

[15] Kings Coll London Sch Med, Dept Haematol Med, London WC2R 2LS, England

[16] Univ Oxford, Nuffield Div Clin Lab Sci, Radcliffe Dept Med, Oxford OX3 9DU, England

[17] Australian Natl Univ, Math Sci Inst, Canberra, ACT 0200, Australia

[18] Prince Wales Hosp, Haematol Dept, South Eastern Area Lab Serv, Randwick, NSW 2031, Australia

[19] Southern Sydney Haematol, Kogarah, NSW 2217, Australia

[20] Royal North Shore Hosp, St Leonards, NSW 2065, Australia

[21] North Coast Canc Inst, Port Macquarie, NSW 2444, Australia

[22] Canberra Hosp, Canberra, ACT 2605, Australia

[23] Concord Repatriat Gen Hosp, Concord, NSW 2139, Australia

[24] Wollongong Hosp, Wollongong, NSW 2521, Australia

[25] St George Hosp, Kogarah, NSW 2217, Australia

[26] Celgene Int, CH-2017 Boudry, Switzerland

[27] UNSW, Ramaciotti Ctr Gene Funct Anal, Sydney, NSW 2052, Australia

[28] Westmead Hosp, Westmead, NSW 2145, Australia

来源：

CELL REPORTS | 2017年 / 20卷 / 03期

基金：

英国医学研究理事会; 英国惠康基金; 瑞典研究理事会;

关键词：

ACUTE MYELOID-LEUKEMIA; CLONAL HEMATOPOIESIS; TET2; MUTATIONS; CANCER CELLS; STEM-CELLS; EXPRESSION; INHIBITORS; IMPACT; AGENTS; TRIAL;

D O I：

10.1016/j.celrep.2017.06.067

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 similar to 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 alpha 5 (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.

引用

页码：572 / 585

页数：14

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