Mechanisms of Chromosomal Translocation

Division Of Clinical Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

A manuscript highlighting DNA double strand breaks that colocalized with chromosome translocation hotspots within the MLL and NUP98 genes, in collaboration with Dr. Andre Nussenzweig, was published in FY 2018, and a follow-up manuscript was published in FY2019. We have also developed an in vivo model in which mice with decreased expression of Mcm2 (Mcm2 hypomorph) develop leukemia, with recurrent copy number alterations (CNA), involving known or suspected cancer-related genes. Nucleotide sequence of the breakpoints, primarily interstitial deletions, revealed features of NHEJ at the deletion junctions, and further showed that the deletions were enriched for mononucleotide repeats, consistent with the possibility that replication fork pausing, caused by limiting amounts of Mcm2 protein, preferentially led to DNA double strand breaks at mononucleotide repeats. These experiments were done in collaboration with CCR colleagues Drs. Meltzer and Nussenzweig, and a manuscript describing these findings has been submitted.