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Genomic Analyses Identify Recurrent MEF2D Fusions in Acute Lymphoblastic Leukemia

Chromosomal rearrangements are initiating events in acute lymphoblastic leukemia (ALL). Here, using RNA-sequencing (RNAseq) 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 1164 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 inhibitors treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukemia, for which new therapeutic approaches should be considered.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001002692 Illumina HiSeq 2000 200
EGAD00001002704 Illumina HiSeq 2000 217
Publications Citations
Genomic analyses identify recurrent MEF2D fusions in acute lymphoblastic leukaemia.
Nat Commun 7: 2016 13331
Targetable kinase gene fusions in high-risk B-ALL: a study from the Children's Oncology Group.
Blood 129: 2017 3352-3361
Aberrant splicing in B-cell acute lymphoblastic leukemia.
Nucleic Acids Res 46: 2018 11357-11369
Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases.
Proc Natl Acad Sci U S A 115: 2018 E11711-E11720
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia.
Nat Genet 51: 2019 296-307
Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen.
Elife 9: 2020 e57858
Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.
Blood 138: 2021 948-958
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.
Blood 139: 2022 3519-3531
Integrative multi-omics and drug response profiling of childhood acute lymphoblastic leukemia cell lines.
Nat Commun 13: 2022 1691
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion.
Blood 140: 2022 1390-1407
The genomic landscape of pediatric acute lymphoblastic leukemia.
Nat Genet 54: 2022 1376-1389
Identification of TCF3 germline variants in pediatric B-cell acute lymphoblastic leukemia.
Blood Adv 7: 2023 2177-2180
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response.
Nat Med 29: 2023 170-179