A new study provides direct evidence that mutations associated with certain forms of leukemia transform blood cells into abnormal cancer cells. The research, published in the February issue of Cancer Cell, examines the molecular signals involved in this transformation and suggests new therapeutic approaches for a rare lethal form of childhood leukemia.
The protein Shp2 is required for normal growth factor and cytokine signaling. Mutations in Shp2 cause Noonan Syndrome (NS), which is associated with an increased risk of juvenile myelomonocytic leukemia (JMML), and Shp2 mutations have been associated with sporadic JMML as well as other leukemias. Dr. M. Golam Mohi, a research fellow from the Neel Laboratory at Beth Israel Deaconess Medical Center, in collaboration with research groups at Brigham and Women's Hospital and Emory University, examined the effect of Shp2 mutants on bone marrow and blood cell proliferation. Leukemia-associated Shp2 mutations caused a fatal leukemia in mice that resembled JMML. The leukemia-associated Shp2 mutants were much more likely to transform bone marrow cells than NS mutants were. The researchers also discovered that Shp2 mutants exhibited a perturbation in Ras signaling, a well-established pathway that plays a key role in governing cell survival and proliferation. Specific inhibitors of Ras/Mek and Tor pathways interfered with mutant Shp2-induced proliferation of abnormal bone marrow progenitor cells, which generate blood cells.
The results presented here establish a causal link between Shp2 mutations and leukemia, and point to leukemia-associated Shp2 mutants as attractive therapeutic targets for human cancers associated with Shp2 mutation. "Current treatments for leukemia caused by Shp2 mutations are often ineffective. Given the frequently lethal outcome of Shp2-associated cancers, clinical trials of currently available Ras/Mek and/or Tor inhibitors should be considered; at least until selective Shp2 inhibitors are developed. Our mouse model of Shp2-evoked myeloproliferative disorder may provide a useful system to test these and other therapeutic approaches," offers Dr. Mohi.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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