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Katherine Vrieze (Berquam)


kberquam@hotmail.com
Mentor: Adam Dupuy, Ph.D.
Lab Room: 1-251 BSB
Lab Phone: 319-335-7606

Our research focuses on identifying driver mutations that contribute to T-cell acute lymphocytic leukemia (T-ALL). We have used the Sleeping Beauty (SB) transposon system to model this disease in mouse. The SB system consists of two parts, the transposons and the transposase, called SBase. The transposons are DNA elements that are mobilized by SBase. They hop around in the genome and can cause mutations when they hop in or near genes. This system is Cre-inducible, and we bred mice that turned on the SB system at different points in T-cell development. Vav-iCre was used to turn the system on in hematopoietic stem cells, Lck-Cre was used to turn the system on double negative thymocytes, and CD4-Cre was used to turn the system on in double positive thymocytes. We then waited for the mice to develop lymphoma, harvested DNA from thymic tissue, and had deep sequencing done to identify the transposon/genomic DNA junctions. Subsequent bioinformatics and data processing allowed us to identify driver mutations in tumors. Driver mutations are those that are contributing to tumor development. We can identify them because they occur at rates higher than background. This is due to positive selection in the tumor.

The mutation profiles gleaned from this screen tell us a lot about T-ALL, but may also give us clues about cancer in general. By creating these three different models of lymphoma we can identify known and novel cancer genes, identify interactions among these genes, and identify novel therapeutic targets. By looking at the mutation profiles of tumors from the models we can also learn how "cell of origin" plays a role in the positive selection of mutations.



Brett BT, Berquam-Vrieze KE, Nannapaneni K, Huang J, Scheetz TE, Dupuy AJ. Novel molecular and computational methods improve the accuracy of insertion site analysis in Sleeping Beauty-induced tumors. PLoS One. 2011;6(9):e24668. Epub 2011 Sep 13. PubMed PMID: 21931803; PubMed Central PMCID: PMC3172244.

Berquam-Vrieze KE, Swing DA, Tessarollo L, Dupuy AJ. Characterization of transgenic mice expressing cancer-associated variants of human NOTCH1. Genesis. 2012 Feb;50(2):112-8. doi: 10.1002/dvg.20798. Epub 2012 Jan 6. PubMed PMID:21898766.

Berquam-Vrieze KE, Nannapaneni K, Brett BT, Holmfeldt L, Ma J, Zagorodna O, Jenkins NA, Copeland NG, Meyerholz DK, Knudson CM, Mullighan CG, Scheetz TE, Dupuy AJ. Cell of origin strongly influences genetic selection in a mouse model of T-ALL. Blood. 2011 Oct 27;118(17):4646-56. Epub 2011 Aug 9. PubMed PMID:21828136; PubMed Central PMCID: PMC3208280.