title: The Kasumi-1 cell line: a t(8;21)-kit mutant model for acute myeloid leukemia.
abstract: The Kasumi-1 cell line is an intensively investigated model system of Acute Myeloid Leukemia with t(8;21) translocation, that represents 1 of the 2 main subtypes of Core Binding Factor Leukemia (CBFL). Since establishment in 1991 the Kasumi-1 cell line has provided the tool to study the peculiar molecular, morphologic, immunophenotypic findings of AML with t(8;21) and the functional consequences of the AML1-ETO fusion oncogene on myeloid differentiation. Leukemogenesis involves multiple genetic changes and, as suggested by murine experiments and other findings in humans, AML1-ETO expression may not be sufficient for full blown leukemia. In agreement with the "two hits" model of leukemogenesis, based on the cooperation between 1 class of mutations that impair hematopoietic differentiation and a second class of mutations that confer a proliferative and/or survival advantage to hematopoietic progenitors an activating mutation in the tyrosine kinase domain of the c-kit gene was identified in the AML1/ETO expressing Kasumi-1 cell line. The dosage of the Asn822Lys mutated allele was shown to be about 5-fold compared to the normal allele and c-kit amplification was found to map to minute 4cen-q11 marker chromosomes, likely derived from the extra chromosome 4 recorded in the newly established cell line. The combination of t(8;21) and trisomy 4 leading to enhanced dosage of a mutated kit allele is a feature of a few CBFL patients reproduced by the Kasumi-1 cell model. The Kasumi-1 cell line, paralleling the commitment stage of CBF leukemia also provides a valuable resource to investigate the effect of tyrosine kinase kit mutant on the main KIT-regulated signal transduction pathways, i.e. MAPK, PI3K/AKT and STAT3 and the diverse inhibitory effect exerted by STI 571 on these KIT mutant activated pathways. PI3K-dependent activation of AKT and STAT activation was observed in Kasumi-1 cells. Contrary to the expectations for an amplified tyrosine kinase kit mutant, we found that STI 571 inhibited KIT Asn822Lys tyrosine phosphorylation and downstream JNK and STAT3 effectors in Kasumi-1 cells, but had no effect on constitutive activation of AKT, suggesting that signaling by tyrosine kinases other than KIT may be responsible for its activation in Kasumi-1 cells. Independent findings on the same model system provide complementary insights into designing strategies for treatment of CBF leukemia associated with mutations in the KIT catalytic domain.
authors.affiliation: Department of Biology and Genetics for Medical Sciences, Medical Faculty, University of Milan, Italy. lidia.larizza@unimi.it
authors.forename: Lidia
authors.initials: L
authors.lastname: Larizza
authors.forename: Ivana
authors.initials: I
authors.lastname: Magnani
authors.forename: Alessandro
authors.initials: A
authors.lastname: Beghini
mesh_terms: D000208:Acute Disease; D045744:Cell Line, Tumor; D002891:Chromosomes, Human, Pair 21; D002898:Chromosomes, Human, Pair 8; D006801:Humans; D007951:Leukemia, Myeloid / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: D019009:Proto-Oncogene Proteins c-kit