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Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia. Nat Commun 2016 11 08;7:13331

Date

11/09/2016

Pubmed ID

27824051

Pubmed Central ID

PMC5105166

DOI

10.1038/ncomms13331

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.

Author List

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 Jr, 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, Mrózek K, Marcucci G, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Paietta E, Willman CL, Loh ML, Hunger SP, Mullighan CG

Author

Michael James Burke MD Professor in the Pediatrics department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Base Sequence
Gene Expression Regulation, Leukemic
Gene Rearrangement
Genomics
Histone Deacetylase Inhibitors
Humans
Luciferases
MEF2 Transcription Factors
Mice
NIH 3T3 Cells
Oncogene Proteins, Fusion
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Sequence Analysis, RNA
Transcriptome
Treatment Outcome
jenkins-FCD Prod-482 91ad8a360b6da540234915ea01ff80e38bfdb40a