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Mutations in PTPN11 implicate the SHP-2 phosphatase in leukemogenesis
Mignon L Loh1, Shashaank Vattikuti, Suzanne Schubbert
1Department of Pediatrics, University of California, Rm HSE-302 Box 0519, San Francisco, CA 94143, USA. lohm@itsa.ucsf.edu
Blood
|December 3, 2003
Summary
Mutations in the PTPN11 gene, encoding SHP-2 phosphatase, are linked to juvenile myelomonocytic leukemia (JMML). These PTPN11 mutations promote myeloid leukemogenesis by impacting Ras signaling pathways.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- The PTPN11 gene encodes SHP-2, a protein tyrosine phosphatase crucial for signal transduction from growth factor receptors to Ras.
- Mutations in PTPN11 are known to cause Noonan syndrome and are associated with hematologic disorders like juvenile myelomonocytic leukemia (JMML).
Purpose of the Study:
- To investigate the role of PTPN11 mutations in myeloid leukemogenesis, specifically in JMML.
- To determine if PTPN11 mutations contribute to the development of myeloid malignancies.
Main Methods:
- Screening of the PTPN11 coding region for mutations in 51 JMML specimens and 60 other myeloid malignancy samples.
- Biochemical analysis of leukemia-associated SHP-2 proteins in engineered Ba/F3 cells.
Main Results:
- Missense mutations in PTPN11 were identified in 16 of 49 JMML specimens (without Noonan syndrome) but were less frequent in other myeloid malignancies.
- PTPN11 mutations were largely mutually exclusive with RAS and NF1 mutations in JMML, suggesting a shared pathway involving Ras.
- Engineered cells expressing leukemia-associated SHP-2 showed enhanced growth factor-independent survival, but key Ras effectors (ERK, Akt) were not hyperactivated.
Conclusions:
- SHP-2 is a significant cellular protein tyrosine phosphatase implicated in myeloid malignancies through mutations.
- Further research is needed to elucidate the precise mechanisms by which mutant SHP-2 proteins interact with Ras and other effectors to drive myeloid growth deregulation.