Mouse models of human AML accurately predict chemotherapy response

Abstract

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.[Keywords: AML; AML1/ETO; MLL; chemotherapy; mouse models] Supplemental material is available at http://www.genesdev.org.

A cluster of cooperating tumor-suppressor gene candidates in chromosomal deletions

“…Intrasplenic injections and bioluminescence imaging for triple-knockdown experiments were performed as described previously (37)(38)(39).…”

Cancer-associated IDH2 mutants drive an acute myeloid leukemia that is susceptible to Brd4 inhibition

“…As underlying differences in survival of patients with different AML genotypes can be linked to treatment response (Zuber et al 2009;Patel et al 2012), we asked whether IDH2 mutant AMLs were intrinsically sensitive or resistant to ara-C chemotherapy. Consistent with previous reports (Zuber et al 2009), Nras G12D ;AML1-ETO leukemic cells were much more sensitive to ara-C than Nras G12D ;MLL-AF9 leukemic cells in a 3-d treatment assay (IC 50 = 39 vs. 63 nM; P = 0.03).…”

“…As underlying differences in survival of patients with different AML genotypes can be linked to treatment response (Zuber et al 2009;Patel et al 2012), we asked whether IDH2 mutant AMLs were intrinsically sensitive or resistant to ara-C chemotherapy. Consistent with previous reports (Zuber et al 2009), Nras G12D ;AML1-ETO leukemic cells were much more sensitive to ara-C than Nras G12D ;MLL-AF9 leukemic cells in a 3-d treatment assay (IC 50 = 39 vs. 63 nM; P = 0.03). In contrast, both Nras G12D ;IDH2 R140Q and Nras G12D ; IDH2 R172K AML cells were highly resistant to ara-C in vitro (IC 50 = 93 and 345 nM, respectively; P = 0.0001 for (H) Kaplan-Meier survival curve of the secondary recipient mice transplanted with Flt3-ITD or Nras G12D HSPCs transduced with IDH2 wild type or mutants (IDH2 R140Q and IDH2 R172K ).…”

“…HSPCs were cultured with stem cell medium as described (Schmitt et al 2002;Zuber et al 2009). IDH2 mutant AMLs were cultured with IMDM medium supplemented with 20% FBS and 0.2 ng/mL IL-3.…”

Entinostat Prevents Leukemia Maintenance in a Collaborating Oncogene-Dependent Model of Cytogenetically Normal Acute Myeloid Leukemia

“…Several leukemia-associated gene rearrangements have been recapitulated in genetically engineered mouse models, some of which have been used successfully to monitor response to therapy and provide insights into chemosensitivity and chemoresistance [10]. Similarly, transduction/transplantation studies have been widely used to recapitulate deregulated oncogene expression in the leukemia setting and provide a basis for functional studies.…”