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Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia

Lookup NU author(s): Professor Anthony MoormanORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.


Publication metadata

Author(s): Gu Z, Churchman M, Roberts K, Li Y, Liu Y, Harvey RC, McCastlain K, Reshmi SC, Payne-Turner D, Iacobucci I, Shao Y, Chen IM, Valentine M, Pei D, Mungall KL, Mungall AJ, Ma Y, Moore R, Marra M, Stonerock E, Gastier-Foster JM, Devidas M, Dai Y, Wood B, Borowitz M, Larsen EE, Maloney K, Mattano LA, Angiolillo A, Salzer WL, Burke MJ, Gianni F, Spinelli O, Radich JP, Minden MD, Moorman AV, Patel B, Fielding AK, Rowe JM, Luger SM, Bhatia R, Aldoss I, Forman SJ, Kohlschmidt J, Mrozek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, Mullighan CG

Publication type: Article

Publication status: Published

Journal: Nature Communications

Year: 2016

Volume: 7

Online publication date: 08/11/2016

Acceptance date: 23/09/2016

Date deposited: 06/01/2017

ISSN (electronic): 2041-1723

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ncomms13331

DOI: 10.1038/ncomms13331


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Funding

Funder referenceFunder name
Leukemia and Lymphoma Society Specialized Center of Research grant
Alex's Lemonade Stand Foundation
American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital
Lady Tata Memorial Trust Award
Leukemia and Lymphoma Society
St. Baldrick's Consortium Award
St. Baldrick's Foundation Scholar Award
Stand Up to Cancer Innovative Research Grant
CA180827NCI
CA145707NCI
CA21765National Cancer Institute
HHSN261200800001ENational Cancer Institute, National Institutes of Health
HHSN261200800001ENCI
U10 CA180820NCI
U10 CA98413NCI
U10 CA98543NCI
U24 CA114737National Cancer Institute
U01 CA157937National Cancer Institute
U10 CA180861NCI
U24 CA114766NCI
U24 CA196171NCI

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