ZMYM2 ‐ FLT3 Fusion Gene: Implications for Chromosomal Instability and Proliferation in Myeloid/Lymphoid Neoplasms

Myeloid/Lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) are rare hematological malignancies often characterized by eosinophilia and the presence of tyrosine kinase gene fusions. Among these, the ZMYM2::FLT3 (Z2F3) fusion gene is an uncommon genetic abnormality found in some MLN-TK patients. This study aimed to investigate the function and underlying mechanisms of the ZMYM2::FLT3 fusion gene identified in a young female patient. Using RNA sequencing, specific primers for PCR, and FISH, we identified and validated the ZMYM2::FLT3 fusion gene in the patient's bone marrow samples, based on which lentiviral vectors containing the fusion gene and negative control were constructed and transfected into the mouse Ba/F3 (BF) cell line to establish stable cell lines. The influence of ZMYM2::FLT3 on the karyotype of the mouse cells was assessed using R-banding analysis. CCK8 assays and flow cytometry in the presence of three tyrosine kinase inhibitors were conducted to investigate cell proliferation and apoptosis. Western blotting was performed to analyze the phosphorylation status of downstream substrates. RNA sequencing identified a fusion of the FLT3 gene at 13q12.2 with the ZMYM2 gene at 13q12.11, subsequently confirmed by PCR, FISH, and Sanger sequencing. The ZMYM2::FLT3 fusion gene conferred interleukin-3 (IL-3) independence on BF cells, significantly enhancing cell proliferation (p < 0.05), increasing cell division rates, and altering chromosomal karyotype composition. ZMYM2::FLT3 affects cell stability and promotes malignant proliferation. All three tested tyrosine kinase inhibitors effectively inhibited the proliferation of cells expressing the ZMYM2::FLT3 fusion gene (p < 0.05), mitigating the fusion gene-induced effects on cell division and chromosomal instability. Additionally, these inhibitors promoted apoptosis in ZMYM2::FLT3-overexpressing cells by reducing the phosphorylation levels of STAT3 and ERK. The ZMYM2::FLT3 fusion gene significantly promotes cell proliferation and genetic instability, and its effects can be mitigated using tyrosine kinase inhibitors.