We previously reported the development of a model of AML in mice induced by the combined expression of a conditionally expressed NRASG12V oncogene and the MLL fusion oncogene MLL-AF9. This mouse model combines a Vav promoter-Tet transactivator (Vav-tTA) transgene, a doxycycline (DOX)-repressible tet-regulated element promoter-NRASG12V (TRE-NRASG12V) transgene, and Mll-AF9 “knock-in” transgene. When we transplanted triple transgenic Vav-tTA; TRE-NRASG12V; Mll-AF9 AML into SCID mice we found that doxycycline (DOX) treatment via the drinking water could prevent AML engraftment or eliminate AML cells after growth to full-blown leukemia. However, these mice eventually develop DOX-resistant AML, which does not re-express the NRASG12V transgene. In more recent data, we find that the Vav-tTA; TRE-NRASG12V; Mll-AF9 AML cells are also Ara-C sensitive as we can repeatedly induce temporary remission in transplant recipients of these cells by 5 day courses of 50 mg/kg Ara-C given once per day intra-peritoneally. Although Ara-C is the backbone of human Ara-C treatment, many patients develop Ara-C resistant AML over time. In our model, fully Ara-C resistant AML develops after 4 to 5 courses of treatment. Nevertheless, a combination of Ara-C treatment and NRASG12V transgene suppression using DOX can extend remission and survival compared to treatment with either approach alone suggesting that some benefit could be obtained by combining RAS pathway inhibitors with conventional chemotherapy. However, even in this case, AML that is resistant to both Ara-C and NRASG12V transgene suppression eventually develops in all mice. Primary AML samples that have been selected in vivo for resistance to Ara-C, NRASG12V oncogene suppression, or both, have been collected and are being analyzed by mRNA microarray for changes in gene expression that might be responsible for the acquisition of resistance.

Disclosures: No relevant conflicts of interest to declare.

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