Mouse models of human AML accurately predict chemotherapy response

Zuber, J., Radtke, I., Pardee, T. S., Zhao, Z., Rappaport, A. R., Luo, W., McCurrach, M. E., Yang, M. M., Dolan, M. E., Kogan, S. C., Downing, J. R., Lowe, S. W. (April 2009) Mouse models of human AML accurately predict chemotherapy response. Genes Dev, 23 (7). pp. 877-89.

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DOI: 10.1101/gad.1771409


The genetic heterogeneity of cancer influences the trajectory of tumor progression and may underlie clinical variation in therapy response. To model such heterogeneity, we produced genetically and pathologically accurate mouse models of common forms of human acute myeloid leukemia (AML) and developed methods to mimic standard induction chemotherapy and efficiently monitor therapy response. We see that murine AMLs harboring two common human AML genotypes show remarkably diverse responses to conventional therapy that mirror clinical experience. Specifically, murine leukemias expressing the AML1/ETO fusion oncoprotein, associated with a favorable prognosis in patients, show a dramatic response to induction chemotherapy owing to robust activation of the p53 tumor suppressor network. Conversely, murine leukemias expressing MLL fusion proteins, associated with a dismal prognosis in patients, are drug-resistant due to an attenuated p53 response. Our studies highlight the importance of genetic information in guiding the treatment of human AML, functionally establish the p53 network as a central determinant of chemotherapy response in AML, and demonstrate that genetically engineered mouse models of human cancer can accurately predict therapy response in patients.

Item Type: Paper
Uncontrolled Keywords: AML AML1/ETO MLL chemotherapy mouse models
Subjects: diseases & disorders > cancer
diseases & disorders
organism description > animal
diseases & disorders > cancer > drugs and therapies > chemotherapy
diseases & disorders > cancer > drugs and therapies
organism description > animal > mammal > primates > hominids > human
diseases & disorders > cancer > cancer types > leukemia
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL labs > Lowe lab
School of Biological Sciences > Publications
Depositing User: Matt Covey
Date: 1 April 2009
Date Deposited: 20 Feb 2013 17:42
Last Modified: 03 Nov 2017 20:12
PMCID: PMC2666344
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