Activation of Proto-Oncogenes by Chromosomal Translocation

Division Of Clinical Sciences - Nci

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Abstract

A large series of pediatric acute myeloid leukemia patients has demonstrated that over 5% of patients have a NUP9::NSD1 fusion, and that this fusion predicts a poor response to chemotherapy. We have cloned a NUP98::NSD1 fusion into the Vav1 expression vector, and generated mice that have incorporated the transgene. Three of the founders developed acute myeloid leukemia. Unexpectedly, acute myeloid leukemia is not increased in the F1 generation. However, it has been noted that most pediatric AML patients with a NUP98::NSD1 fusion have a concomitant FLT3-ITD mutation. When vav1-NUP98::NSD1 mice were crossed to mice that expressed a Flt3-ITD, over 70% of mice developed AML, indicating an in vivo collaboration between these two mutations. A manuscript describing these findings was published in FY 2023. In collaboration with Dr. Munira Basrai of the Genetics branch, we have generated mice that overexpress CENPA in the hematopoietic compartment. CENPA overexpression in yeast and cultured cell lines leads to chromosomal mis-segregation; the transgenic mice will enable us to determine if the mis-segregation takes place in primary cells as well. Moreover, CENPA overexpression has been linked to several malignancies, these mice will enable us to determine if CENPA overexpression is oncogenic in vivo. A portion of these results were published in FY2021. Preliminary experiments indicated that T and B cell lymphomas that developed in mice that overexpress CENPA on a TP53 deficient background have increased aneuploidy; we are in the process of confirming these observations using an orthogonal approach.