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RasGRP1 overexpression in T-ALL increases basal nucleotide exchange on Ras rendering the Ras/PI3K/Akt pathway
O Ksionda1, A A Melton1,2, J Bache3
1Department of Anatomy, Roose University of California, San Francisco, San Francisco, CA, USA.
Oncogene
|November 10, 2015
Summary
This study reveals a new mechanism of Ras signaling in T-cell acute lymphoblastic leukemia (T-ALL) driven by Ras guanine nucleotide-releasing protein 1 (RasGRP1). This RasGRP1-driven pathway differs from KRAS mutations and involves increased Ras GTP/GDP cycling.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Ras GTPases are key regulators of cell signaling, activated by RasGEFs and inactivated by RasGAPs.
- Somatic mutations in RAS genes, like KRAS(G12D), are common in metastatic cancers.
- Overexpression of Ras guanine nucleotide-releasing protein 1 (RasGRP1) is implicated in pediatric T-cell acute lymphoblastic leukemia (T-ALL).
Purpose of the Study:
- To investigate the mechanism of Ras signaling in RasGRP1-driven T-ALL.
- To compare Ras signaling in RasGRP1 T-ALL with normal thymocytes and KRAS(G12D) T-ALL.
- To elucidate the role of diacylglycerol (DAG) and interleukins (ILs) 2, 7, and 9 in RasGRP1 T-ALL.
Main Methods:
- Analysis of Erk and Akt pathway activation downstream of Ras in response to IL-2/7/9 stimulation.
- Investigation of RasGRP1 recruitment to the membrane and its dependence on phospholipase C-γ (PLCγ) and DAG.
- Assessment of Ras GTP-loading rates using three distinct assays to measure the RasGTP/GDP cycle.
Main Results:
- IL-2/7/9 stimulation activates Erk and Akt pathways in RasGRP1 T-ALL but not normal thymocytes.
- Leukemic Ras-Akt signaling relies on baseline DAG levels, not acute PLCγ activation.
- RasGRP1 overexpression in T-ALL leads to a constitutively high Ras GTP-loading rate, unlike KRAS(G12D) T-ALL.
Conclusions:
- A novel Ras signaling mechanism in T-ALL is identified, driven by RasGRP1 and characterized by increased Ras GTP/GDP cycling.
- This RasGRP1-driven pathway is mechanistically distinct from KRAS(G12D)-driven oncogenesis.
- Interleukin signaling in T-ALL may involve decreased RasGAP activity, highlighting the dynamic RasGEF/RasGAP balance.
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