Mouse models of human AML accurately predict chemotherapy response.
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.
Zuber
Johannes
J
Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
Radtke
Ina
I
Pardee
Timothy S
TS
Zhao
Zhen
Z
Rappaport
Amy R
AR
Luo
Weijun
W
McCurrach
Mila E
ME
Yang
Miao-Miao
MM
Dolan
M Eileen
ME
Kogan
Scott C
SC
Downing
James R
JR
Lowe
Scott W
SW