Dysregulated RasGRP1 Responds to Cytokine Receptor Input in T Cell Leukemogenesis

Sci Signal. 2013 Mar 26;6(268):ra21. doi: 10.1126/scisignal.2003848.

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-Ras(G12D). Leukemia screens in wild-type mice, but not in mice expressing the mutant K-Ras(G12D) that encodes a constitutively active Ras, yielded frequent retroviral insertions that led to increased Rasgrp1 expression. Rasgrp1 and oncogenic K-Ras(G12D) promoted T-ALL through distinct mechanisms. In K-Ras(G12D) 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cell Cycle Checkpoints / genetics
  • Cell Cycle Checkpoints / physiology
  • Cell Proliferation
  • Child
  • DNA Primers / genetics
  • Diglycerides
  • Enzyme Activation / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / physiology*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Humans
  • Mice
  • Models, Biological
  • Mutagenesis, Insertional
  • Oligonucleotides / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / physiology*
  • ras Proteins / metabolism*

Substances

  • DNA Primers
  • Diglycerides
  • Guanine Nucleotide Exchange Factors
  • Oligonucleotides
  • RNA, Small Interfering
  • Rasgrp1 protein, mouse
  • ras Proteins