NEW YORK (Reuters Health) - The Shp2 protein is required for growth factor and cytokine signaling, and Shp2 mutations are known to play a role in various forms of leukemia. Now, for the first time, researchers have identified the specific effects of Shp2 mutants on hematopoiesis.
The findings are reported in the February issue of Cancer Cell by a multicenter team led by Dr. M. Golam Mohi of the Beth Israel Deaconess Medical Center in Boston.
Shp2 mutations are associated with leukemias for which currently available treatments are generally ineffective. For example, Shp2 mutations cause Noonan syndrome, which confers an increased risk for the rapidly progressive and difficult-to-treat juvenile myelomonocytic leukemia.
In a murine model of leukemia, the investigators discovered that Shp2 mutations cause leukemia by directly transforming primary myeloid progenitors.
In addition, the authors were able to prove that Shp2 mutants cause myeloproliferation in Drosophila, and thus “subvert a highly conserved pathway regulating myeloid cell proliferation/survival.”
The authors also discovered that mutations associated with Noonan Syndrome and leukemia “have intrinsically different potencies for myeloid transformation, which may have prognostic implications for Noonan syndrome patients.”
According to the investigators, several agents being tested in clinical trials may turn out to be useful singly or in combination for patients with Shp2 mutations, including Mek inhibitors, inhibitors of the upstream kinase Raf, Tor inhibitors and rapamycin.
“Given the often fatal outcome of juvenile myelomonocytic leukemia and other Shp2-associated neoplasms, clinical trials of Mek and/or Tor inhibitors should be considered, at least until selective Shp2 inhibitors are developed,” the investigators conclude.
Source: Cancer Cell 2005;7:179-191. [ Google search on this article ]
MeSH Headings:Animal Diseases: Disease Models, Animal: etiology: DiseasesCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
