ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype

Fusion genesinvolving ZNF384have recently been identified in B-cell precursor acute lymphoblasticleukemia, and 7 fusion partners have been reported. We further characterized this type of fusion geneby whole transcriptome sequencing and/or polymerase chain reaction. In addition to previously reported genes, we identified BMP2Kas a novel fusion partner for ZNF384. Including the EP300- ZNF384that we reported recently, the total frequency of ZNF384-related fusion geneswas 4.1% in 291 B-cell precursor acute lymphoblasticleukemia patients enrolled in a single clinical trial, and TCF3- ZNF384was the most recurrent, with a frequency of 2.4%. The characteristic immunophenotypeof weak CD10 and aberrant CD13 and/or CD33expression was revealed to be a common feature of the leukemic cells harboring ZNF384-related fusion genes. The signature gene expression profile in TCF3- ZNF384-positive patients was enriched in hematopoietic stem cell features and related to that of EP300- ZNF384-positive patients, but was significantly distinct from that of TCF3-PBX1 -positive and ZNF384-fusion-negative patients. However, clinical features of TCF3- ZNF384-positive patients are markedly different from those of EP300- ZNF384-positive patients, exhibiting higher cell counts and a younger age at presentation. TCF3- ZNF384-positive patients revealed a significantly poorer steroid response and a higher frequency of relapse, and the additional activating mutations in RAS signaling pathway genes were detected by whole exome analysis in some of the cases. Our observations indicate that ZNF384-related fusion genesconsist of a distinct subgroup of B-cell precursor acute lymphoblasticleukemia with a characteristic immunophenotype, while the clinical features depend on the functional properties of individual fusion partners.