Leukemia Research 37 (2013) 175–182 Contents lists available at SciVerse ScienceDirect Leukemia Research jo ur nal homep age: www.elsevier.com/locate/leukres Dasatinib inhibits proliferation and induces apoptosis in the KASUMI-1 cell line bearing the t(8;21)(q22;q22) and the N822K c-kit mutation Vassiliki E. Mpakou a , Frieda Kontsioti a , Sotiris Papageorgiou a , Aris Spathis b , Christine Kottaridi b , Kostas Girkas a , Petros Karakitsos b , George Dimitriadis a , Ioannis Dervenoulas a , Vasiliki Pappa a,∗ a Second Department of Internal Medicine and Research Institute, Attikon University Hospital, Rimini 1, Haidari, Athens 12462, Greece b Cytology Department, Attikon University Hospital, Rimini 1, Haidari, Athens 12462, Greece a r t i c l e i n f o Article history: Received 6 June 2012 Received in revised form 11 October 2012 Accepted 15 October 2012 Available online 10 November 2012 Keywords: Acute myeloid leukemia Apoptosis Dasatinib Kasumi-1 c-kit VEGF/VEGFR-2 pathway a b s t r a c t Activating mutations of the c-kit gene are frequently found in CBF (core binding factor) leukemias. We evaluated the effect of tyrosine kinase inhibitor dasatinib in leukemic cell lines bearing or not c-kit mutations. Our data demonstrate that in the AML Kasumi-1 cell line, bearing the N822K c-kit muta- tion, dasatinib is a potent suppressor of c-kit and Src kinase activity and inhibits the phosphorylation of their downstream target AKT, possibly through the Src-mediated VEGF/VEGFR receptor type 2 path- way. Dasatinib also effectively blocks proliferation and induces apoptosis through caspase-3 activation in Kasumi-1 cells. These data further encourage the integration of dasatinib in the treatment of CBF AML with c-kit mutations in the context of clinical trials, which are eagerly anticipated. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction Acute myeloid leukemia (AML) accounts for approximately 30% of all adult leukemias and is considered as a clonal hematopoi- etic disorder, characterized by the accumulation of myeloblasts in the bone marrow and blood [1]. AML includes a large vari- ety of clonal chromosomal abnormalities and is described as a disease with great heterogeneity, deriving from both, cytoge- netic alterations and molecular mutations. The development of AML is the result of several complementing mutations, among which those leading to the constitutive activation of signal transduction pathways (class I mutations), such as mutations in the receptor tyrosine kinases (RTKs) c-kit and Flt3 resulting in enhanced hematopoietic stem cell survival and proliferation [2]. Activating mutations of the c-kit gene are frequently found in CBF (core binding factor) leukemias [3], reported in a range of 12.8–46.1% of adult CBFL (core binding factor leukemia) [4,5]. CBF leukemia with t(8;21)(q22;q22) occurs in approximately 8% of patients with de novo AML and clinically shows a high rate of com- plete remission (CR) and prolonged CR duration [6,7]. However, c-kit activation loop mutations (e.g. substitution of D816 in exon ∗ Corresponding author. Tel.: +30 210 5832549. E-mail address: vas pappa@yahoo.com (V. Pappa). 17) in CBFL seem to be associated with inferior event-free survival, relapse-free survival, cumulative incidence of relapse and overall survival [5,8,9]. Dasatinib (BMS-354825) is an ATP-competitive agent, designed as a dual SRC/ABL inhibitor that targets a variety of tyrosine kinases, most notably the Src family (c-Src, Lck, Fyn, Lyn and Yes) and the BCR/ABL fusion protein with an IC 50 of <1 nmol/l [10–13]. Other tyrosine kinases inhibited by dasatinib include c-kit, Ephrin recep- tors (EphA and EphB) and platelet-derived growth factor (PDGF) receptor [3,11]. Dasatinib has proved effective in imatinib-resistant chronic myeloid leukemia (CML) by inhibiting BCR/ABL activa- tion loop mutations [14,15] through binding both the active and inactive form of BCR/ABL [16–18]. The drug has been already approved for clinical use in imatinib resistant or -intolerant CML as well as for the treatment of Philadelphia chromosome positive (Ph + ) acute lymphoblastic leukemia (ALL) resistant or intolerant to imatinib [10,13]. More importantly, based on the results of the DASISION trial, dasatinib has been recently approved as a first line treatment of chronic phase chronic myelogenous leukemia [19]. Based on the above, we evaluated the efficacy of dasatinib in inhibiting cell proliferation and promoting apoptosis in leukemic cell lines bearing or not c-kit mutations with the view to provide experimental data allowing the addition of the drug to the ther- apeutic armamentarium of c-kit mutant CBF AMLs known to be associated with inferior prognosis. 0145-2126/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2012.10.011