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Unformatted text preview: Proc. Natl.Acad. Sci. USA Vol.93,pp.4742-4749, May 1996 Medical Sciences ThiscontributionispartofthespecialseriesofInauguralArticlesbymembers oftheNationalAcademy ofSciences electedonApril25,1995. The control of hematopoiesis and leukemia: From basic biology to the clinic LEO SACHS Department ofMolecularGenetics,Weizmann InstituteofScience,Rehovot 76100,Israel ContributedbyLeo Sachs, March 11, 1996 ABSTRACT Hematopoiesis gives rise to blood cells of different lineages throughout normal life.Abnormalities in this developmental program lead toblood celldiseases in- cludingleukemia.The establishmentofacellculturesystem for the clonal development of hematopoietic cells made it possibletodiscoverproteinsthatregulatecellviability,mul- tiplicationand differentiationofdifferenthematopoieticcell lineages, and the molecular basis ofnormal and abnormal blood celldevelopment. These regulators include cytokines nowcalledcolony-stimulatingfactors(CSFs)andinterleukins (ILs).There isanetworkofcytokineinteractions,which has positiveregulators such as CSFs and ILsand negativeregu- lators such as transforming growth factor f3 and tumor necrosisfactor(TNF).Thismultigenecytokinenetworkpro- vides flexibilitydepending on which part ofthe network is activatedandallowsamplificationofresponsetoaparticular stimulus. Malignancy can be suppressed incertain types of leukemiccellsbyinducingdifferentiationwithcytokinesthat regulatenormalhematopoiesisorwithothercompounds that use alternative differentiation pathways. This created the basis for the clinical use of differentiation therapy. The suppression of malignancy by inducing differentiation can bypass genetic abnormalities that give rise to malignancy. Different CSFs and ILs suppress programmed cell death (apoptosis)andinducecellmultiplicationanddifferentiation, and theseprocessesofdevelopmentare separatelyregulated. The same cytokinessuppressapoptosisinnormaland leuke- mic cells, including apoptosis induced by irradiation and cytotoxiccancer chemotherapeutic compounds. An excess of cytokines can increase leukemic cellresistance to cytotoxic therapy. The tumor suppressor gene wild-type p53 induces apoptosis that can also be suppressed by cytokines. The oncogene mutant p53 suppresses apoptosis. Hematopoietic cytokinessuchasgranulocyteCSF are now usedclinicallyto correct defects inhematopoiesis, includingrepairofchemo- therapy-associated suppression ofnormal hematopoiesis in cancer patients, stimulation ofnormal granulocyte develop- ment in patients with infantile congenital agranulocytosis, andincreaseofhematopoieticprecursorsforbloodcelltrans- plantation.Treatments thatdecrease the levelofapoptosis- suppressingcytokinesanddownregulateexpressionofmutant p53 and other apoptosis suppressing genes in cancer cells couldimprovecytotoxiccancertherapy.The basicstudieson hematopoiesis and leukemia have thus provided new ap- proaches totherapy....
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