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CSHL team develops mouse models of leukemia that predict response to chemotherapy
Date:3/31/2009

trolled by the p53 gene, a linchpin of the cell's anti-tumor defense response, as the key determinant of AML's aggressiveness and response to therapy.

Most patients with AML receive the same standardized treatment an initial phase of intense chemotherapy followed by additional chemotherapy cycles or bone marrow transplantation. Yet only a quarter of patients are cured and most die within a few months. This diversity in treatment response is due to AML's genetic heterogeneity, meaning that the hundred or so mutations associated with this form of cancer occur in different combinations in each patient and influence therapeutic outcomes in different ways.

Some gene mutations in cancer have been correlated with clinical outcome. But AML has proved to be genetically too complex, and the current experimental systems for predicting treatment response too unreliable for the information to be used in a standard way in the clinic.

These standard systems, in which anticancer drugs were tested in human cancer-cell lines, do not factor in the effects of a real tumor's environment on its growth. At the same time, placing these cells into animals to create a so-called "xenotransplant" model has not been an effective solution, according to Johannes Zuber, M.D., a Clinical Fellow in the Lowe lab who played a key role in the research and is first author on the team's paper. The reason, explains Zuber, is that "the cells are so poorly defined at the genetic level and tend to defy analysis of the molecular factors that influence drug response."

Making mice with human-like AML

Lowe's group surmounted these problems by first identifying the most commonly occurring mutations in a group of 111 children with AML and then engineering these mutations into mice, which soon developed leukemia. Among the participating AML patients, the two most common mutations were observed to occur when chromosomes broke apart and reattached in new places
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Contact: Hema Bashyam
bashyam@cshl.edu
516-367-6822
Cold Spring Harbor Laboratory
Source:Eurekalert

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