The long-locked door to combating low platelet counts _ especially inpatients suffering side effects of irradiation and chemotherapy _ hasopened.Several groups of scientists report the discovery and cloning of thecytokine responsible for platelet development in a series of four articlesin today's issue of Nature. Prior to these papers, only the cell-surfacereceptor for the cytokine was known. Now the structure and function ofthrombopoietin (TPO _ the humoral regulator of blood plateletproduction) itself is described.It is vital to restore platelets because people with abnormally lowcirculating platelet numbers are at risk for severe and devastatinghemorrhage.Platelets _ small blood cell fragments that break off from a relativelyhuge parent cell (the megakaryocyte) _ are key to normal bloodclotting. They routinely serve as patches for small defects in bloodvessels to confine hemorrhage and encourage ordinary coagulation.Vast numbers of platelets aggregate to form a thrombus that stopsexcessive bleeding at wound sites.If platelets could be maintained at normal levels by administering TPO,it may be possible to provide patients with higher and potentiallycurative doses of standard cancer drugs without the limiting sideeffects. Recent clinical trial successes with other colony stimulatingfactors (CSF) serve as a model for encouraging the development ofplatelet-stimulating drugs as adjunctive therapy for cancer patients.Now it may become possible to design TPO drugs that not only restoreplatelets which are destroyed by chemical therapy but to treat a varietyof diseases such as leukemia, autoimmune disorders, viral infectionssuch as HIV, sepsis as well as transplant rejection.TPO completes biotechnology's arsenal of cytokines to treatdeficiency's of the three fundamental components of blood: red bloodcells, white blood cells, granulocyte-macrophages and platelets.Erythropoietin (EPO) regulates the development of red blood cells andvarious CSFs such as granulocyte CSF and granulocyte-macrophageCSF to control the maturation of other blood cell types. Plateletsmature under the direction of the newest clinical candidate in thecytokine family _ TPO.Isolation, Purification Of FactorEver since TPO was recognized about 30 years ago, scientists havebeen laboring to identify the factor that would stimulate plateletproduction. But isolation and purification of the factor eludeddiscovery _ until now _ because conventional methods werechallenged by the very meager concentrations of starting material athand in the plasma. In the work described in Nature, the cytokinereceptor was the starting point used to finally capture the elusive ligand_ the TPO cytokine.In one of the Nature articles entitled "Stimulation ofmegakaryocytopoiesis and thrombopoiesis by the c-Mpl ligand," DanEaton and his colleagues at South San Francisco-based Genentech Inc.and the Mayo Clinic in Rochester, Minn., initially purified thecytokine, then isolated the human clone and determined the nucleicacid sequence of the cytokine that stimulates platelets. The protein wasexpressed to confirm that the cDNA did, in fact, code for the c-Mplligand. The major conclusion is that the c-Mpl ligand is actually thelong-sought-after cytokine."This discovery represents a potential major clinical advance in theareas of hematology and oncology," said Barry Sherman, Genentech'svice president and chief medical officer. "The new growth factor islikely to be useful in the rapidly expanding field of bone marrowtransplantation, in which thrombocytopenia [low platelet counts] is amajor complication."The c-Mpl is a proto-oncogene that codes for an orphan cytokinereceptor which regulates megakaryocytopoiesis (the developmentalprocess generating platelets). TPO has both molecular and functionalhomology with EPO. Unlike most other cytokines that either stimulatedivision of progenitor cells or alternatively affect the maturationprocess, TPO influences both.A second paper entitled "cMpl ligand is a humoral regulator ofmegakaryocytopoiesis," by Francoise Wendling, colleagues at theInstitut Gustave Roussy in Villejuif, France, and at Immunex Corp. ofSeattle, reports that the cytokine is active in the blood of severalspecies including rats, dogs and pigs, in addition to humans. Theevidence strongly suggests that the Mpl ligand (TPO) and themegakaryocyte-specific cytokine (MK-CSF) are in fact the samemolecule.Finally, a pair of papers by scientists from ZymoGenetics Corp., ofSeattle, and the University of Washington offer a more detailed portraitof the platelet-stimulating factor and show that the cytokine promptsbone marrow megakaryocyte precursors to differentiate and matureinto platelets. In the article entitled "Cloning and sequencing of murinethrombopoietin and stimulation of platelet production in vivo," DonaldFoster and his colleagues at ZymoGenetics along with KennethKaushansky and his University of Washington group report the cloningof a murine cDNA that codes for TPO.A sister paper by the same lab groups, "Promotion of megakaryocyteprogenitor expansion and differentiation by the c-mpl ligandthrombopoietin" suggests that the maturation of megakaryocytes maybegin with interleukin 3 and may be completed by the c-Kit ligand. Thec-Kit, which is another proto-oncogene, induces later stages of plateletdevelopment including division, cytoplasmic expansion, membranematuration and platelet release.Although these discoveries in the four papers are vastly significant,Donald Metcalf, of the Walter and Eliza Hall Institute of MedicalResearch in Victoria, Australia, cautions that expectations shouldremain realistic."A regulator needs target cells to elicit a response, and the badlydamaged marrow of a patient after intensive chemotherapy may wellno longer contain enough targets to allow maximum possible plateletresponse," he wrote in an editorial appearing in the same issue ofNature. n'
-- Bonnie Joy Sedlak Special To BioWorld Today
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