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To: scaram(o)uche who wrote (1099)	12/4/1999 1:28:00 PM
From: Miljenko Zuanic	Respond to of 4974

Mol Cell Biol 1999 Nov;19(11):7473-80 BCR/ABL directly inhibits expression of SHIP, an SH2-containing polyinositol-5-phosphatase involved in the regulation of hematopoiesis. Sattler M, Verma S, Byrne CH, Shrikhande G, Winkler T, Algate PA, Rohrschneider LR, Griffin JD Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. martin_sattler@dfci.harvard.edu The BCR/ABL oncogene causes chronic myelogenous leukemia (CML), a myeloproliferative disorder characterized by clonal expansion of hematopoietic progenitor cells and granulocyte lineage cells. The SH2-containing inositol-5-phosphatase SHIP is a 145-kDa protein which has been shown to regulate hematopoiesis in mice. Targeted disruption of the murine SHIP gene results in a myeloproliferative syndrome characterized by a dramatic increase in numbers of granulocyte-macrophage progenitor cells in the marrow and spleen. Also, hematopoietic progenitor cells from SHIP(-/-) mice are hyperresponsive to certain hematopoietic growth factors, a phenotype very similar to the effects of BCR/ABL in murine cells. In a series of BCR/ABL-transformed hematopoietic cell lines, Philadelphia chromosome (Ph)-positive cell lines, and primary cells from patients with CML, the expression of SHIP was found to be absent or substantially reduced compared to untransformed cell lines or leukemia cells lacking BCR/ABL. Ba/F3 cells in which expression of BCR/ABL was under the control of a tetracycline-inducible promoter showed rapid loss of p145 SHIP, coincident with induction of BCR/ABL expression. Also, an ABL-specific tyrosine kinase inhibitor, CGP57148B (STI571), rapidly caused reexpression of SHIP, indicating that BCR/ABL directly, but reversibly, regulates the expression of SHIP protein. The estimated half-life of SHIP protein was reduced from 18 h to less than 3 h. However, SHIP mRNA also decreased in response to BCR/ABL, suggesting that SHIP protein levels could be affected by more than one mechanism. Reexpression of SHIP in BCR/ABL-transformed Ba/F3 cells altered the biological behavior of cells in culture. The reduction of SHIP due to BCR/ABL is likely to directly contribute to the pathogenesis of CML.

To: scaram(o)uche who wrote (1099)	12/4/1999 2:19:00 PM
From: sim1	Respond to of 4974

Drug shows promise against one form of leukemia cnn.com NEW ORLEANS (CNN) -- Cancer researchers on Friday reported dramatic results in early clinical trials of an experimental pill designed to combat chronic myelogenous leukemia, one of four common forms of leukemia. The drug has few side effects and may have the potential to destroy other cancers, medical experts said. The findings are being presented in New Orleans, at the annual meeting of the American Society of Hematology. In a study of 37 patients treated with the drug, code-named STI-571, all of them had complete normalization of their blood counts, signaling a remission of their leukemia. "In every single one of them, their blood counts have returned to normal within one month of starting therapy and (in) a significant number of them, we've actually seen the molecular cause of this leukemia begin to disappear," said one of the researchers, Dr. Brian Druker of Oregon Health Sciences University. 'Too good to be true' Unlike traditional, toxic chemotherapy treatments, which kill both cancerous and healthy cells, STI-571 specifically targets an enzyme found only in leukemia cells, meaning patients suffer minimal side effects. In one phase of the experiment, chronic myelogenous leukemia (CML) patients with early stages of the disease who failed to respond to traditional interferon treatment received STI-571 in pill form once a day. Patients experienced little or no toxicity, and most of those receiving doses at 200 mg or higher had white cell blood counts come down to normal, researchers said. They said the molecular cause of CML begin to disappear at doses of 300 mg or more. "One of the problems I've had with this project is that I often times have difficulty convincing people that this isn't too good to be true," Druker told CNN. 'Literally given me my life back' Leukemia patient Virginia Garner, who was dying from leukemia just months ago and did not respond to interferon, is enthusiastic about the experimental drug. "(It) has no side effects whatsoever. It's literally given me my life back," she told CNN. Chronic myelogenous leukemia, which prevents blood cells from maturing normally, is more common in middle-aged and elderly people. The only major symptom is extreme fatigue. The end stage of the disease, known as the blast crisis, can be fatal within several months. More tests needed Some experts think the preliminary success of STI-571 shows the treatment for chronic myelogenous leukemia could work for other cancers as well. "We're hopeful that opening this new door will result in a cure of chronic myelogenous leukemia and thus pave the way for additional drug developments in cancer," said Dr. Harmon Eyre, chief medical officer of the American Cancer Society. Before that can happen, though, researchers say they need more time to see if the preliminary results hold up under long-term studies with more patients. The next phase of testing, involving 19 medical centers in the United States and Europe, is set to begin this month. The study was funded by the National Institutes of Health, the Leukemia Society, and Novartis, a pharmaceutical company. Medical Correspondent Rhonda Rowland contributed to this report.