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.
The Kasumi-1 cell line : a t(8;21)-kit mutant model for acute myeloid leukemia / L. Larizza, I. Magnani, A. Beghini. - In: LEUKEMIA & LYMPHOMA. - ISSN 1042-8194. - 46:2(2005 Feb), pp. 247-255.
|Titolo:||The Kasumi-1 cell line : a t(8;21)-kit mutant model for acute myeloid leukemia|
LARIZZA, LIDIA (Primo)
MAGNANI, IVANA (Secondo)
BEGHINI, ALESSANDRO (Ultimo)
|Parole Chiave:||c-kit activating mutation; c-kit amplification; Core Binding Factor Leukemia; Kasumi-1 cell line; KIT mutant-mediated signal transduction; STI 571; t(8;21)|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||feb-2005|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1080/10428190400007565|
|Appare nelle tipologie:||01 - Articolo su periodico|