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Sci. Signal., 26 March 2013
Vol. 6, Issue 268, p. ra21
[DOI: 10.1126/scisignal.2003848]

RESEARCH ARTICLES

Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Catherine Hartzell1*, Olga Ksionda1*, Ed Lemmens1*, Kristen Coakley1, Ming Yang2, Monique Dail3, Richard C. Harvey4, Christopher Govern2, Jeroen Bakker1, Tineke L. Lenstra1, Kristin Ammon3, Anne Boeter1, Stuart S. Winter5, Mignon Loh3, Kevin Shannon3, Arup K. Chakraborty2,6,7,8,9, Matthias Wabl10, and Jeroen P. Roose1{dagger}

1 Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
2 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
3 Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
4 Department of Pathology, University of New Mexico School of Medicine, MSC 10 5590, Albuquerque, NM 87131, USA.
5 Department of Pediatrics, University of New Mexico School of Medicine, MSC 10 5590, Albuquerque, NM 87131, USA.
6 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
7 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
8 Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
9 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
10 Department of Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

* These authors contributed equally to this work.

Abstract: Enhanced signaling by the small guanosine triphosphatase Ras is common in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), but the underlying mechanisms are unclear. We identified 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 with KRAS and NRAS mutations, 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.

{dagger} Corresponding author. E-mail: jeroen.roose{at}ucsf.edu

Citation: C. Hartzell, O. Ksionda, E. Lemmens, K. Coakley, M. Yang, M. Dail, R. C. Harvey, C. Govern, J. Bakker, T. L. Lenstra, K. Ammon, A. Boeter, S. S. Winter, M. Loh, K. Shannon, A. K. Chakraborty, M. Wabl, J. P. Roose, Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis. Sci. Signal. 6, ra21 (2013).

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