Using the Zebrafish to Investigate the Role of the NUP98-NSD1 Oncogene and Loss of NUP98 in High-Risk Pediatric Acute Myeloid Leukemia

Abstract

Many genetic mutations lead to acute myeloid leukemia (AML), including the translocation NUP98-NSD1 (NND1), which is found primarily in pediatric AML and causes high-risk disease. There is currently no animal model of the NND1 translocation and consequential loss of endogenous NUP98, even though the loss of NUP98 may also affect leukemogenesis. I genetically engineered two zebrafish: a transgenic expressing human NND1, and another with decreased nup98. Zebrafish embryos with both genetic aberrations displayed disrupted blood development akin to myelodysplastic syndrome (MDS): decreased erythrocyes, decreased early and differentiated myeloid cells, and increased hemtoapoietic stem cells (HSCs). Adult transgenic fish also showed disrupted blood development, similar to MDS and AML, with decreased erythrocytes and lymphocytes, and increased myeloid cells and precursor cells. These results suggest that NUP98-NSD1 is causing impaired cellular differentiation, which may be manifesting as a myelodysplastic syndrome (MDS). These zebrafish models provide new preclinical platforms to test targeted therapies.