Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.
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.
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Zhaohui
Z
Gu
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Michelle
M
Churchman
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Kathryn
K
Roberts
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Yongjin
Y
Li
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Yu
Y
Liu
University of New Mexico Cancer Center, Albuquerque, New Mexico 87106, USA.
Richard C
RC
Harvey
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Kelly
0000-0001-7868-3049
K
McCastlain
The Research Institute, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.
Shalini C
SC
Reshmi
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Debbie
D
Payne-Turner
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Ilaria
I
Iacobucci
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.|Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Ying
Y
Shao
University of New Mexico Cancer Center, Albuquerque, New Mexico 87106, USA.
I-Ming
IM
Chen
Cytogenetic Shared Resource, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Marcus
M
Valentine
Department of Biostatistics, St Jude Children's Research Hospital, Memphis, Tennessee 38105.
Deqing
D
Pei
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
Karen L
KL
Mungall
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
Andrew J
0000-0002-0905-2742
AJ
Mungall
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
Yussanne
Y
Ma
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
Richard
R
Moore
Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
Marco
M
Marra
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.|Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Eileen
E
Stonerock
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, Ohio 43205, USA.|Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.|Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43210, USA.
Julie M
JM
Gastier-Foster
Department of Biostatistics, Colleges of Medicine and Public Health &Health Professions, University of Florida, Gainesville, Florida 32611, USA.
Meenakshi
M
Devidas
Department of Biostatistics, Colleges of Medicine and Public Health &Health Professions, University of Florida, Gainesville, Florida 32611, USA.
Yunfeng
Y
Dai
Department of Laboratory Medicine, University of Washington, Seattle, Washington 98195, USA.
Brent
B
Wood
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA.
Michael
M
Borowitz
Maine Children's Cancer Program, Scarborough, Maine 04074, USA.
Eric E
EE
Larsen
Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado 80045, USA.
Kelly
K
Maloney
HARP Pharma Consulting, Mystic, Connecticut 06355, USA.
Leonard A
LA
Mattano
Children's National Medical Center, Washington, DC 20010, USA.
Anne
A
Angiolillo
US Army Medical Research and Materiel Command, Fort Detrick, Maryland 21702, USA.
Wanda L
0000-0002-7820-9635
WL
Salzer
Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Michael J
MJ
Burke
Department of Hematology and Bone Marrow Transplantation, Papa Giovanni XXIII Hospital Piazza OMS 1 24127, Bergamo, Italy.
Francesca
F
Gianni
Department of Hematology and Bone Marrow Transplantation, Papa Giovanni XXIII Hospital Piazza OMS 1 24127, Bergamo, Italy.
Orietta
O
Spinelli
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Jerald P
JP
Radich
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
Mark D
MD
Minden
Leukemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
Anthony V
AV
Moorman
Department of Haemato-Oncology, Barts Cancer Institute, London EC1M 6BQ, UK.
Bella
B
Patel
Department of Hematology, UCL Cancer Institute, London WC1E 6BT, UK.
Adele K
AK
Fielding
Hematology, Shaare Zedek Medical Center, Jerusalem 9103102, Israel.
Jacob M
JM
Rowe
Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Selina M
SM
Luger
Division of Hematology and Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Ravi
R
Bhatia
Division of Hematology and Oncology, Department of Medicine, The University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
Ibrahim
I
Aldoss
Gehr Family Center for Leukemia Research, City of Hope, Duarte, California 91010, USA.
Stephen J
SJ
Forman
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
Jessica
J
Kohlschmidt
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Krzysztof
K
Mrózek
Gehr Family Center for Leukemia Research, City of Hope, Duarte, California 91010, USA.
Guido
G
Marcucci
The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Clara D
CD
Bloomfield
University of Chicago Medical Center, Chicago, Illinois 60637, USA.
Wendy
W
Stock
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Steven
S
Kornblau
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hagop M
HM
Kantarjian
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Marina
M
Konopleva
Cancer Center, Montefiore Medical Center North Division, Bronx, New York 10467, USA.
Elisabeth
E
Paietta
University of New Mexico Cancer Center, Albuquerque, New Mexico 87106, USA.
Cheryl L
CL
Willman
Department of Pediatrics, Benioff Children's Hospital, San Francisco, California 94158, USA.|Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94115, USA.
Mignon L
ML
Loh
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.|Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Stephen P
SP
Hunger
Department of Pathology and Hematological Malignancies Program, St Jude Children's Research Hospital, 262 Danny Thomas Place, MS 342, Memphis, Tennessee 38105, USA.
Charles G
0000-0002-1871-1850
CG
Mullighan
D000818:Animals; D001483:Base Sequence; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement / Q000235:genetics; D023281:Genomics / Q000379:methods*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D064326:MEF2 Transcription Factors / Q000235:genetics; D051379:Mice; D041681:NIH 3T3 Cells; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D017423:Sequence Analysis, RNA; D059467:Transcriptome; D016896:Treatment Outcome
D056572:Histone Deacetylase Inhibitors; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; D015514:Oncogene Proteins, Fusion; D008156:Luciferases