TCF3::ZNF384 induces steroid resistance in B‐cell precursor acute lymphoblastic leukemia cells

Abstract Background ZNF384 rearrangements ( ZNF384 ‐r) are associated with distinct subgroups of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL) and the mixed phenotype of acute leukemia. Types of BCP‐ALL with ZNF384 ‐r exhibit common immunophenotypic characteristics, whereas their clinical features are not uniform and TCF3::ZNF384 ‐positive patients show a significantly poorer steroid response and higher frequency of relapse, while EP300::ZNF384 ‐positive patients exhibit a favorable response to conventional chemotherapy. Therefore, we aimed to investigate the differences in biological effects between these two ZNF384‐r molecules. Method We transduced BCP‐ALL cell lines with both TCF3::ZNF384 and EP300::ZNF384 by retrovirus‐mediated gene transduction, and examined the biological effects. Results Flow cytometric analysis and RT‐qPCR revealed down‐regulation of CD10 in BCP‐ALL cells after transduction with both TCF3::ZNF384 and EP300::ZNF384. The annexin‐V binding apoptosis assay indicated that TCF3::ZNF384‐, but not EP300::ZNF384‐, expressing cells exhibited increased resistance to dexamethasone‐induced apoptosis. By means of an oligonucleotide microarray and RT‐qPCR, we observed that the transduction of TCF3::ZNF384 , but not EP300::ZNF384 , leads to significant enhancement of cyclin D2 ( CCND2 ) gene expression in BCP‐ALL cells, but no growth advantage was observed. Conclusion Our data suggest that the acquisition of dexamethasone resistance in BCP‐ALL cell lines is an effect of TCF3::ZNF384 protein distinct from EP300::ZNF384. Other than the common functions of ZNF384‐r that contribute to the development of leukemia with a lineage‐ambiguous phenotype, TCF3::ZNF384 may exhibit a fusion partner‐dependent function distinct from EP300::ZNF384 and participate in the formation of characteristic clinical features of TCF3 :: ZNF384 ‐expressing ALL patients.