Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

被引：229

作者：

Gu, Zhaohui ^{[1
,2
]}

Churchman, Michelle ^{[1
,2
]}

Roberts, Kathryn ^{[1
,2
]}

Li, Yongjin ^{[3
]}

Liu, Yu ^{[3
]}

Harvey, Richard C. ^{[4
]}

McCastlain, Kelly ^{[1
,2
]}

Reshmi, Shalini C. ^{[5
]}

Payne-Turner, Debbie ^{[1
,2
]}

Iacobucci, Ilaria ^{[1
,2
]}

Shao, Ying ^{[1
,2
,3
]}

Chen, I-Ming ^{[4
]}

Valentine, Marcus ^{[6
]}

Pei, Deqing ^{[7
]}

Mungall, Karen L. ^{[8
]}

Mungall, Andrew J. ^{[8
]}

Ma, Yussanne ^{[8
]}

Moore, Richard ^{[8
]}

Marra, Marco ^{[8
]}

Stonerock, Eileen ^{[9
,10
,11
]}

Gastier-Foster, Julie M. ^{[9
,10
,11
]}

Devidas, Meenakshi ^{[12
,13
]}

Dai, Yunfeng ^{[12
,13
]}

Wood, Brent ^{[14
]}

Borowitz, Michael ^{[15
]}

Larsen, Eric E. ^{[16
]}

Maloney, Kelly ^{[17
,18
]}

Mattano, Leonard A., Jr. ^{[19
]}

Angiolillo, Anne ^{[20
]}

Salzer, Wanda L. ^{[21
]}

Burke, Michael J. ^{[22
]}

Gianni, Francesca ^{[23
]}

Spinelli, Orietta ^{[23
]}

Radich, Jerald P. ^{[24
]}

Minden, Mark D. ^{[25
]}

Moorman, Anthony V. ^{[26
]}

Patel, Bella ^{[27
]}

Fielding, Adele K. ^{[28
]}

Rowe, Jacob M. ^{[29
]}

Luger, Selina M. ^{[30
]}

Bhatia, Ravi ^{[31
]}

Aldoss, Ibrahim ^{[31
]}

Forman, Stephen J. ^{[32
]}

Kohlschmidt, Jessica ^{[33
,34
,35
]}

Mrozek, Krzysztof ^{[33
]}

Marcucci, Guido ^{[32
]}

Bloomfield, Clara D. ^{[33
]}

Stock, Wendy ^{[36
]}

Kornblau, Steven ^{[37
]}

Kantarjian, Hagop M. ^{[37
]}

机构：

[1] St Jude Childrens Res Hosp, Dept Pathol, 262 Danny Thomas Pl,MS 342, Memphis, TN 38105 USA

[2] St Jude Childrens Res Hosp, Hematol Malignancies Program, 262 Danny Thomas Pl,MS 342, Memphis, TN 38105 USA

[3] St Jude Childrens Res Hosp, Dept Computat Biol, 332 N Lauderdale St, Memphis, TN 38105 USA

[4] Univ New Mexico, Ctr Canc, Albuquerque, NM 87106 USA

[5] Nationwide Childrens Hosp, Res Inst, Columbus, OH 43205 USA

[6] St Jude Childrens Res Hosp, Cytogenet Shared Resource, 332 N Lauderdale St, Memphis, TN 38105 USA

[7] St Jude Childrens Res Hosp, Dept Biostat, 332 N Lauderdale St, Memphis, TN 38105 USA

[8] BC Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada

[9] Nationwide Childrens Hosp, Dept Pathol & Lab Med, Columbus, OH 43205 USA

[10] Ohio State Univ, Coll Med, Dept Pathol, Columbus, OH 43210 USA

[11] Ohio State Univ, Dept Pediat, Coll Med, Columbus, OH 43210 USA

[12] Univ Florida, Dept Biostat, Coll Med, Gainesville, FL 32611 USA

[13] Univ Florida, Dept Biostat, Coll Publ Hlth & Hlth Profess, Gainesville, FL 32611 USA

[14] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA

[15] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA

[16] Maine Childrens Canc Program, Scarborough, ME 04074 USA

[17] Univ Colorado, Sch Med, Pediat Hematol Oncol BMT, Aurora, CO 80045 USA

[18] Childrens Hosp Colorado, Aurora, CO 80045 USA

[19] HARP Pharma Consulting, Mystic, CT 06355 USA

[20] Childrens Natl Med Ctr, Washington, DC 20010 USA

[21] US Army, Med Res & Mat Command, Ft Detrick, MD 21702 USA

[22] Med Coll Wisconsin, Milwaukee, WI 53226 USA

[23] Papa Giovanni XXIII Hosp Piazza OMS 1, Dept Hematol & Bone Marrow Transplantat, I-24127 Bergamo, Italy

[24] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA

[25] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 2M9, Canada

[26] Newcastle Univ, Leukemia Res Cytogenet Grp, Northern Inst Canc Res, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England

[27] Barts Canc Inst, Dept Haematooncol, London EC1M 6BQ, England

[28] UCL Canc Inst, Dept Hematol, London WC1E 6BT, England

[29] Shaare Zedek Med Ctr, Hematol, IL-9103102 Jerusalem, Israel

[30] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA

[31] Univ Alabama Birmingham, Dept Med, Div Hematol & Oncol, Birmingham, AL 35294 USA

[32] City Hope Natl Med Ctr, Gehr Family Ctr Leukemia Res, Duarte, CA 91010 USA

[33] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA

[34] Mayo Clin, Alliance Clin Trials Oncol Stat, Rochester, MN 55905 USA

[35] Mayo Clin, Ctr Data, Rochester, MN 55905 USA

[36] Univ Chicago, Med Ctr, Chicago, IL 60637 USA

[37] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA

[38] Montefiore Med Ctr, Ctr Canc, North Div, 111 E 210th St, Bronx, NY 10467 USA

[39] Benioff Childrens Hosp, Dept Pediat, San Francisco, CA 94158 USA

[40] Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94115 USA

[41] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA

[42] Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

美国国家卫生研究院;

关键词：

FORKHEAD BOX J2; GENE-EXPRESSION; BREAST-CANCER; IDENTIFICATION; TRANSFORMATION; MEF2D/DAZAP1; MIGRATION; CLONING; KINASE; CRLF2;

D O I：

10.1038/ncomms13331

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.

引用

页数：10

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