Mechanisms of Chromosomal Translocation

Division Of Clinical Sciences - Nci

Investigators

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Abstract

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. These experiments were done in collaboration with CCR colleagues Drs. Meltzer and Nussenzweig, and manuscripts describing these findings were published in FY2020 and FY2023 (PMID: 35920299. 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. Preliminary results from this study are encouraging, as we have detected focal, pronounced (20-fold) copy number gains of Dhfr and Abcb1a (previously designated MDR1) associated with resistance to methotrexate and vincristine respectively. 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.