Abstract A56: Loss of wild-type Kras promotes oncogenic Kras-induced leukemogenesis

Although the Ras genes have long been established as proto-oncogenes, substantial evidence indicates that wild-type (WT) Ras genes act as tumor suppressors in a few solid tumor models. However, recent study by Shannon group discovers that loss of WT Nras does not further promote oncogenic Nras-induced leukemias (Xu et al ., 2013), raising the possibility that the earlier finding of WT Ras genes as tumor suppressors restricts to specific Ras isoform(s) and/or specific cell types. Here, we show that in mouse cell lines established from oncogenic Kras-induced acute T-cell lymphoblastic leukemia/lymphoma (T-ALL), WT Kras expression is absent or significantly downregulated due to deletion or epigenetic silencing of the locus. Moreover, WT Kras allele is deleted in ∼30% of primary Kras G12D T-ALL samples but not in pre-leukemia specimens. Our results are consistent with a recent study that WT KRAS allele is deleted in early-stage progenitor ALL patients with an oncogenic KRAS mutation (Zhang, et al ., 2012), suggesting that loss of WT Kras expression is a pathological mechanism contributing to T-ALL progression. To test our hypothesis, we generated compound mice carrying a conditional Kras G12D allele, a floxed WT Kras allele and the Mx1-Cre allele. In the absence of pIpC induction, the leaky expression of Cre is sufficient to induce both oncogenic Kras G12D activation and WT Kras deletion in ∼50% of HSCs. We find that Kras G12D/- mice have a much shorter life span than Kras G12D/+ mice and display more severe leukemia phenotypes, including splenomegaly, leukocytosis, thrombocytopenia, and increase of monocytic cells in peripheral blood and spleen. Bone marrow transplantation experiment confirms that loss of WT Kras promotes oncogenic Kras-induced leukemias in a cell-autonomous manner. Further studies demonstrate that loss-of-WT Kras attenuates Kras G12D HSC depletion and enhances GM-CSF signaling in Kras G12D hematopoietic stem/progenitor cells (HSPCs). We are continuously working on the underlying mechanisms. Taken together, our study elucidates the cross-talk between WT and oncogenic Kras in leukemogenesis and provides mechanistic insights of the WT Kras function as a tumor suppressor. Citation Format: Yuan-I Chang, Alisa Damnernsawad, Guangyao Kong, Yangang Liu, Qiang Chang, Jing Zhang. Loss of wild-type Kras promotes oncogenic Kras-induced leukemogenesis. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A56. doi: 10.1158/1557-3125.RASONC14-A56