Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Zhaohui Gu, Michelle Churchman, Kathryn Roberts, Yongjin Li, Yu Liu, Richard C. Harvey, Kelly McCastlain, Shalini C. Reshmi, Debbie Payne-Turner, Ilaria Iacobucci, Ying Shao, I-Ming Chen, Marcus Valentine, Deqing Pei, Karen L. Mungall, Andrew J. Mungall, Yussanne Ma, Richard Moore, Marco Marra, Eileen Stonerock, Julie M. Gastier-Foster, Meenakshi Devidas, Yunfeng Dai, Brent Wood, Michael Borowitz, Eric E. Larsen, Kelly Maloney, Leonard A. Mattano, Anne Angiolillo, Wanda L. Salzer, Michael J. Burke, Francesca Gianni, Orietta Spinelli, Jerald P. Radich, Mark D. Minden, Anthony V. Moorman, Bella Patel, Adele K. Fielding, Jacob M. Rowe, Selina M. Luger, Ravi Bhatia, Ibrahim Aldoss, Stephen J. Forman, Jessica Kohlschmidt, Krzysztof Mrózek, Guido Marcucci, Clara D. Bloomfield, Wendy Stock, Steven Kornblau, Hagop M. Kantarjian, Marina Konopleva, Elisabeth Paietta, Cheryl L. Willman, Mignon L. Loh, Stephen P. Hunger and Charles G. Mullighan ()
Additional contact information
Zhaohui Gu: St Jude Children’s Research Hospital
Michelle Churchman: St Jude Children’s Research Hospital
Kathryn Roberts: St Jude Children’s Research Hospital
Yongjin Li: St Jude Children’s Research Hospital
Yu Liu: St Jude Children’s Research Hospital
Richard C. Harvey: University of New Mexico Cancer Center
Kelly McCastlain: St Jude Children’s Research Hospital
Shalini C. Reshmi: The Research Institute, Nationwide Children’s Hospital
Debbie Payne-Turner: St Jude Children’s Research Hospital
Ilaria Iacobucci: St Jude Children’s Research Hospital
Ying Shao: St Jude Children’s Research Hospital
I-Ming Chen: University of New Mexico Cancer Center
Marcus Valentine: Cytogenetic Shared Resource, St Jude Children’s Research Hospital
Deqing Pei: St Jude Children’s Research Hospital
Karen L. Mungall: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Andrew J. Mungall: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Yussanne Ma: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Richard Moore: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Marco Marra: Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency
Eileen Stonerock: Nationwide Children’s Hospital
Julie M. Gastier-Foster: Nationwide Children’s Hospital
Meenakshi Devidas: Colleges of Medicine and Public Health & Health Professions, University of Florida
Yunfeng Dai: Colleges of Medicine and Public Health & Health Professions, University of Florida
Brent Wood: University of Washington
Michael Borowitz: Johns Hopkins Medical Institutions
Eric E. Larsen: Maine Children’s Cancer Program
Kelly Maloney: Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children’s Hospital Colorado
Leonard A. Mattano: HARP Pharma Consulting
Anne Angiolillo: Children's National Medical Center
Wanda L. Salzer: US Army Medical Research and Materiel Command
Michael J. Burke: Medical College of Wisconsin
Francesca Gianni: Papa Giovanni XXIII Hospital
Orietta Spinelli: Papa Giovanni XXIII Hospital
Jerald P. Radich: Fred Hutchinson Cancer Research Center
Mark D. Minden: Princess Margaret Cancer Centre, University Health Network
Anthony V. Moorman: Leukemia Research Cytogenetics Group, Northern Institute for Cancer Research, Newcastle University
Bella Patel: Barts Cancer Institute
Adele K. Fielding: UCL Cancer Institute
Jacob M. Rowe: Hematology, Shaare Zedek Medical Center
Selina M. Luger: Abramson Cancer Center, University of Pennsylvania
Ravi Bhatia: The University of Alabama at Birmingham
Ibrahim Aldoss: The University of Alabama at Birmingham
Stephen J. Forman: Gehr Family Center for Leukemia Research, City of Hope
Jessica Kohlschmidt: The Ohio State University Comprehensive Cancer Center
Krzysztof Mrózek: The Ohio State University Comprehensive Cancer Center
Guido Marcucci: Gehr Family Center for Leukemia Research, City of Hope
Clara D. Bloomfield: The Ohio State University Comprehensive Cancer Center
Wendy Stock: University of Chicago Medical Center
Steven Kornblau: The University of Texas MD Anderson Cancer Center
Hagop M. Kantarjian: The University of Texas MD Anderson Cancer Center
Marina Konopleva: The University of Texas MD Anderson Cancer Center
Elisabeth Paietta: Cancer Center
Cheryl L. Willman: University of New Mexico Cancer Center
Mignon L. Loh: Benioff Children’s Hospital
Stephen P. Hunger: Children’s Hospital of Philadelphia
Charles G. Mullighan: St Jude Children’s Research Hospital

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms13331

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