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TCF3::ZNF384 induces steroid resistance in B-cell precursor acute lymphoblastic leukemia cells
Shinpei Kusano1,2, Hitomi Ueno-Yokohata1, Momoka Hori1,3
1Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Japan.
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.
