| Hyperactivation of RAS, either by oncogenic mutations of RAS genes or by mutations of genes that regulate RAS, is common in human cancers. We have previously shown that palmitoylation is essential for NRAS leukemogenesis in mice. The results suggest that targeting RAS palmitoylation may be an effective therapy for NRAS associated cancers. We further demonstrated that palmitoylation-deficient oncogenic NRAS is mislocalized away from the plasma membrane yet remains capable of binding GTP in cells. This finding suggests that palmitoylation-deficient RAS may have a dominant negative effect in RAS signaling. In this study we demonstrate that expression of palmitoylation-deficient oncogenic and wild-type NRAS (NRASD12 and wtNRAS) significantly impedes progression of BCR/ABL induced B-acute lymphoblastic lymphoma (B-ALL)- and chronic myeloid leukemia (CML)-like diseases in mice, albeit via different mechanisms. We demonstrated that only palmitoylation-deficient wtNRAS can suppress the activation of signaling through the RAS/RAF/MEK/ERK pathway. These results establish that palmitoylation-deficient NRASD12 and wtNRAS both mitigate BCR/ABL-induced leukemia and suggest that targeting RAS palmitoylation may also constitute an effective therapy in hematological malignancies and other cancers driven by hyperactivation of RAS by upstream effectors such as BCR/ABL. In addition, we found that wild-type NRAS functions as a tumor suppressor in BCR/ABL-mediated leukemogenesis and also that role of palmitoylation is required in activated RAS isoforms KRAS4A, NRAS, and HRAS for cytokine-independent growth. |
