Mechanisms of Chromosomal Translocation

Division Of Clinical Sciences - Nci

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Abstract

Previous work highlighting DNA double strand breaks that colocalized with chromosome translocation hotspots within the MLL and NUP98 genes, done in collaboration with Dr. Andre Nussenzweig, was previously published. We recently 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 was recently published. As discussed in detail under Collaborative Pathways that Lead to Leukemia [ZIA BC 010982], mice that are deficient for Mcm2 develop a specific mutator phenotype, that involves recurrent, acquired DNA copy number losses. These losses can both inactivate tumor suppressor genes (CDKN1A, PTEN) as well as activate oncogenes (Notch1), and lead to B and T cell leukemias in mice. Less commonly, the leukemias that develop in Mcm2 hypomorphic mice are accompanied by copy number gains; one recurrent gain that we have characterized leads to a fusion between Nup214 and Abl1; of note, Nup214-Abl1 fusions are recurrent events associated with B and T-ALL in humans. We are pursuing the mechanisms by which Mcm2 deficiency leads to this mutator/deletor phenotype by using a CRISPR-mediated structure/function assessment of Mcm2. In addition, it is well-established that many leukemias are initially sensitive to chemotherapy, but ultimately develop resistance. We have a panel of Mcm2 deficient and control, Mcm2 proficient T-ALL cell lines. We are in the process of developing derivatives of this panel of cell lines that are chemotherapy resistant. Chemotherapy resistant cell lines will then be assayed for acquired SNV and CNA, to determine important events in developing chemotherapy resistance. Chromosomal translocations, and the mechanisms by which they occur, are highly relevant for childhood cancer. In fact, one of the cancer moonshot goals Fusion Oncoproteins in Childhood Cancers (FusOnC2) is focused on fusion oncoproteins. Fusion oncoproteins are well-known, critical driver mutations in a wide spectrum of childhood cancers, from leukemias including acute myeloid leukemia to childhood sarcomas, to thyroid tumors. The vast majority of fusion oncoproteins are produced by recurrent, non-random chromosomal translocations.