Activation of Proto-Oncogenes by Chromosomal Translocation

Division Of Clinical Sciences - Nci

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Abstract

CENPA overexpression has been linked to several malignancies, and CENPA overexpression in yeast and cultured cell lines leads to chromosomal mis-segregation and subsequent aneuploidy. In collaboration with Dr. Munira Basrai of the Genetics branch, we generated mice that overexpress CENPA in the hematopoietic compartment to determine if the mis-segregation takes place in primary cells as well. However, these mice did not show clear evidence for mis-segregation, nor did they develop leukemia. Given that cells deficient in TP53 tolerate aneuploidy better than WT cells, we generated mice that overexpress CENPA in a Trp53 deficient background. Initial finding from these experiments indicated an earlier onset of malignancy and a greater degree of aneuploidy involving specific chromosomes in Trp53 deficient cells that overexpress CENPA compared to Trp53 deficient cells without CENPA overexpression. Ongoing studies are aimed at determining which chromosomes will be consistently gained or lost in vivo. We have previously established that mice which express a NUP98::HOXD13 (NHD13) fusion transgene develop myelodysplastic neoplasm (MDS). We have used in vivo assays of purified hematopoietic subsets to identify an MDS initiating cell (MIC), analogous to a leukemia initiating cell. Surprisingly, the most potent MIC resided in a committed cell population, as opposed to a normal hematopoietic stem cell population. This study was published in FY2025 (PMID: 40614733).