Leukemia advance online publication, 25 November 2011 (doi: 10.1038/leu.2011.328).
Oki, T.,Kitaura, J.,Watanabe-Okochi, N.,Nishimura, K.,Maehara, A.,Uchida, T.,Komeno, Y.,Nakahara, F.,Harada, Y.,Sonoki, T.,Harada, H.& Kitamura, T.
“Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis.”
Mutations in two signaling-related genes play a disproportionate role in the onset and progression of leukemia.
Mutations in the gene encoding the signaling protein called Notch are a common culprit in T cell acute lymphoblastic leukemia/lymphoma (T-ALL). Some mutations are sufficient to induce transformation by themselves, but 50–70% of T-ALL tumors contain milder Notch1 mutants that play a supporting role relative to driver mutations in other genes.
Research led by Toshio Kitamura of Japan’s University of Tokyo has identified one such factor. Various studies indicated that increased expression of RasGRP1 or RasGRP4 — both members of the Ras guanyl-nucleotide releasing protein family — can promote onset of blood cancer, although the relative contributions of these genes to T-ALL remained unclear.
A comparative analysis performed by Kitamura and his colleagues revealed RasGRP1 as the key contributor. Relative to RasGRP4, RasGRP1 was far more likely to induce T-ALL in a mouse model. Accordingly, RasGRP1 overexpression was broadly observed in a small panel of T-ALL patient samples, while RasGRP4 expression was generally unchanged.
RasGRP1 promoted aggressive growth in cultured immune cells, both independently and in conjunction with other known cancer triggers. Notch hyperactivation cooperatively accelerated T-ALL progression in mice receiving transplants of RasGRP1-overexpressing blood cell precursors. Collectively, these results suggest that future T-ALL therapeutics may benefit by disrupting the dangerous collaborative efforts of these two oncogenes.
