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

Fusion genes involving <i>MEF2D</i> 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 remain unknown. We identified 16 cases of acute lymphoblastic leukemia and 1 of lymphoma harboring <i>MEF2D</i> fusions, including <i>MEF2D-BCL9</i> (n=10), <i>MEF2D-HNRNPUL1</i> (n=6), and one novel <i>MEF2D-HNRNPH1</i> fusion. The incidence of <i>MEF2D</i> fusions overall was 2.4% among consecutive precursor B-cell acute lymphoblastic leukemia patients enrolled onto a single clinical trial. They frequently showed a cytoplasmic μ chain-positive pre-B immunophenotype, and often expressed an aberrant CD5 antigen. Besides up- and down-regulation of <i>HDAC9</i> and <i>MEF2C</i>, elevated <i>GATA3</i> expression was also a characteristic feature of <i>MEF2D</i> fusion-positive patients. Mutations of <i>PHF6</i>, recurrent in T-cell acute lymphoblastic leukemia, also showed an unexpectedly high frequency (50%) in these patients. <i>MEF2D</i> fusion-positive patients were older (median age 9 years) with elevated WBC counts (median: 27,300/ml) at presentation and, as a result, were mostly classified as NCI high risk. Although they responded well to steroid treatment, <i>MEF2D</i> fusion-positive patients showed a significantly worse outcome, with 53.3% relapse and subsequent death. Stem cell transplantation was ineffective as salvage therapy. Interestingly, relapse was frequently associated with the presence of <i>CDKN2A/CDKN2B</i> gene deletions. Our observations indicate that <i>MEF2D</i> fusions comprise a distinct subgroup of precursor B-cell acute lymphoblastic leukemia with a characteristic immunophenotype and gene expression signature, associated with distinct clinical features.