Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies
Abstract
Genetic mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2) are associated with childhood leukemias and solid tumors. The mechanisms by which Ptpn11 mutations induce malignancies are not fully understood. In this study, we demonstrate that Ptpn11 disease mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. This finding reveals a novel mechanism by which deregulation of Shp2 induces malignancies and has important clinical implications. Given that Ptpn11 mutations enhance DNA damage-induced tumorigenesis, caution should be taken when considering DNA-damaging preconditioning for stem cell transplantation therapy or DNA-damaging chemotherapy for Ptpn11-associated malignancies, especially in Noonan syndrome patients with germ-line Ptpn11 mutations, as the risk of therapy-induced malignancies in these patients may be increased.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- January 2016
- DOI:
- 10.1073/pnas.1508535113
- Bibcode:
- 2016PNAS..113..984L