The BCR/ABL oncogene is the causative agent in over 95% of cases of chronic myelogenous leukemia (CML). Therapies targeting the ABL kinase have proven to be extremely effective in treating patients with chronic phase CML. However, mutations in the kinase domain tend to occur over time resulting in drug resistance. Therefore, it is important to continue to unravel the complicated network of interactions involved in BCR/ABL-mediated leukemogenesis.

We used two approaches to elucidate potential critical effectors of BCR/ABL. First, we examined the ability of NRASG12D to "rescue" CML-induction by a BCR/ABL^Y177F mutant that is hindered in its ability to induce leukemogenesis. We found that NRASG12D efficiently induces a rapid and fatal CML-like MPD in this BCR/ABL^Y177F background. The assay was repeated with NRASG12D effector mutants T35S (MAPK), E37G (RALGDS), or Y40C (PI3K). This line of inquiry revealed that the RALGDS pathway is the most efficient at inducing a rapid and fatal CML-like MPD. This was confirmed by a complementary approach whereby a dominant negative RAL mutant was inserted downstream of BCR/ABL. This resulted in a delay of disease onset by about two days.

In the second approach, we compared the myeloid and lymphoid leukemogenic potential of two ABL oncogenes with different fusion partners: BCR/ABL and TEL/ABL. Under conditions favoring myeloid proliferation, TEL/ABL induces either a rapid small bowel disease or a CML-like MPD with a long latency. Interestingly, under conditions favoring lymphoid expansion, TEL/ABL is incapable of inducing lymphoid leukemia while BCR/ABL efficiently induces a fatal B-ALL. One obvious difference between these two oncogenes is the ability of TEL/ABL to directly bind TEL, a putative tumor suppressor. TEL is normally localized to the nucleus. Here we showed that TEL localization is altered in the presence of ABL oncogenes.

The results presented within suggest a role for the involvement of the RALGDS pathway and TEL protein in BCR/ABL-mediated leukemogenesis.