Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion

Fusion genesinvolving MEF2D have recently been identified in precursor B-cell acute lymphoblastic leukemia, mutually exclusive of the common risk stratifying genetic abnormalities, although their true incidence and associated clinical characteristics remains unknown. We identified 16 acute lymphoblasticleukemia cases and 1 lymphoma case harboring MEF2D fusions, including MEF2D- BCL9(n=10), MEF2D-HNRNPUL1 (n=6) and one novel MEF2D-HNRNPH1 fusion. The incidence of MEF2D fusions overall was 2.4% among consecutive B-cell acute lymphoblastic leukemiapatients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotypeand often expressed an aberrant CD5antigen. Besides up- and down-regulation of HDAC9and MEF2C, elevated GATA3expression was also a characteristic feature of MEF2D fusions-positive patients. Mutations of PHF6 , recurrent in T-cell acute lymphoblasticleukemia, also showed an unexpectedly high frequency (50%) in these patients. MEF2D fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/μl) at presentation, and, as a result, were mostly classified as NCI high-risk. Although they responded well to steroid treatment, MEF2D fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as a salvage therapy. Interestingly, relapse was frequently associated with the presence of CDKN2A/ CDKN2Bgene deletions. Our observations indicate that MEF2D fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemiawith a characteristic immunophenotypeand gene expression signature, associated with distinct clinical features.