Increased fitness in bone marrow stem cells that overexpress the Ras activator RasGRP1

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The Roose lab at UCSF is part of the Bakar ImmunoX Immunology program (https://immunox.ucsf.edu/) as well as the UCSF Helen Diller Family Comprehensive Cancer Center (http://cancer.ucsf.edu/). In the Roose lab we focus on understanding how different flavors of receptor triggered Ras-kinase signals drive normal developmental processes of various cell types and organ systems and how (and why) perturbations of Ras-kinase signals cause human disease. See http://rooselab.ucsf.edu/.

 

In this current manuscript in Oncogene we investigated the impact of leukemic Ras signals in the bone marrow. Oncogenic mutations in Ras genes themselves, like KRasG12D, trap Ras in the active, GTP-loaded state in hematopoietic cells, just like in other tumor types. Inducible expression of KRasG12D in the bone marrow causes an acute myeloproliferative disease in mice, which progresses to acute myeloid leukemia with a T-cell leukemia in the background. NRasG12D in the bone marrow of mice causes a chronic myeloproliferative disorder. We had observed that patients with T-cell Acute lymphoblastic leukemia (T-ALL) often display abnormal levels of the Ras activator RasGRP1. In the past we have reported on the molecular mechanism of overexpressed RasGRP1, causing constant loading of Ras with GTP, but not trapping Ras in the GTP-loaded state. Cell biologically, it had remained unclear how overexpression of RasGRP1 may impact hematopoiesis in the bone marrow. We generated a novel mouse model, RoLoRiG, allowing for inducible overexpression of RasGRP1. Fortunately, we added an ires-GFP cassette in the targeted Rosa26 locus so that GFP reports on the genetic event of recombined LoxP sites as well as overexpression of RasGRP1. With this novel mouse model we demonstrated that one-time recombination events in a fraction of bone marrow cells results in entirely GFP-positive bone marrow over time. Intriguingly, the increased fitness phenotype in hematopoietic stem cells with RasGRP1-ires-GFP is only observed in the native hematopoiesis and not in bone marrow transplantation assays into irradiated hosts. Capitalizing on a large leukemia virus insertion study, we discuss how overexpression of RasGRP1 can probably pair with several different other genetic events to contribute to T-ALL.

 

For more details see:

https://www.nature.com/articles/s41388-020-01469-8.epdf?sharing_token=c6Wq5C0fLlhAnXd8C6DFgtRgN0jAjWel9jnR3ZoTv0Mbj0EpQvBzTG9PBFouVnridDI9b96DRa6PnoFis9e6M4RwkyXETUcvyKbUXAVKFPVr6tZFCNfB5_o7tkfSBBQCd1yHBDEHn3yvaPACDEugDhSFz6c2DtmUYVYCm-Rvpvk%3D

Jeroen Roose

Professor, UCSF

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