Dysregulated RasGRP1 responds to cytokine receptor input in T cell leukemogenesis

Catherine Hartzell, Olga Ksionda, Ed Lemmens, Kristen Coakley, Ming Yang, Monique Dail, Richard C. Harvey, Christopher Govern, Jeroen Bakker, Tineke L. Lenstra, Kristin Ammon, Anne Boeter, Stuart S. Winter, Mignon Loh, Kevin Shannon, Arup K. Chakraborty, Matthias Wabl, Jeroen P. Roose

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlyingmechanisms are unclear.Weidentified the guanine nucleotide exchange factor RasGRP1 (Rasgrp1 in mice) as a Ras activator that contributes to leukemogenesis. We found increased RasGRP1 expression in many pediatric T-ALL patients, which is not observed in rare early T cell precursor T-ALL patients withKRASandNRASmutations, such as K-RasG12D.Leukemia screens in wild-type mice, but not in mice expressing the mutant K-RasG12D that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression.Rasgrp1 and oncogenic K-RasG12D promoted T-ALL through distinct mechanisms. In K-RasG12D T-ALLs, enhanced Ras activation had to be uncoupled from cell cycle arrest to promote cell proliferation. In mouse T-ALL cells with increased Rasgrp1 expression, we found that Rasgrp1 contributed to a previously uncharacterized cytokine receptor- activated Ras pathway that stimulated the proliferation of T-ALL cells in vivo, which was accompanied by dynamic patterns of activation of effector kinases downstream of Ras in individual T-ALLs. Reduction of Rasgrp1 abundance reduced cytokine-stimulated Ras signaling and decreased the proliferation of T-ALL in vivo. The position of RasGRP1 downstream of cytokine receptors as well as the different clinical outcomes that we observed as a function of RasGRP1 abundance make RasGRP1 an attractive future stratification marker for T-ALL.

Original languageEnglish
Pages (from-to)ra21
JournalScience Signaling
Volume6
Issue number268
DOIs
StatePublished - 26 Mar 2013
Externally publishedYes

Funding

FundersFunder number
National Institute of Allergy and Infectious DiseasesR01AI041570

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