Research ArticleCancer

Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Science Signaling  26 Mar 2013:
Vol. 6, Issue 268, pp. ra21
DOI: 10.1126/scisignal.2003848

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Targeting a Ras Activator in T-ALL

Aberrant Ras signaling is common in many cases of T cell acute lymphoblastic leukemia/lymphoma (T-ALL); however, only a small percentage of T-ALL cases involve activating mutations in Ras, which suggests that Ras activity must be enhanced by other mechanisms. In a screen of 107 pediatric T-ALL patients, Hartzell et al. found heterogeneous expression of the gene encoding the Ras activator RasGRP1 but not of genes encoding seven other Ras activators. In mouse T-ALL cell lines characterized by enhanced Rasgrp1 expression, increased Rasgrp1 abundance enhanced Ras signaling and increased proliferation of T-ALL cells transplanted into nude mice. Knockdown of Rasgrp1 reduced the proliferative potential of these cells in vitro and reduced tumor growth in recipient mice. Although the underlying reason for enhanced Rasgrp1 expression remains unclear, these findings demonstrate that activating mutations in Ras or dysregulated Rasgrp1 abundance generate distinct biochemical signatures in T-ALL and suggest that Rasgrp1 may be a fruitful stratification marker for T-ALL.