Premium
BCR‐ABL‐independent and RAS / MAPK pathway‐dependent form of imatinib resistance in Ph‐positive acute lymphoblastic leukemia cell line with activation of EphB4
Author(s) -
Suzuki Momoko,
Abe Akihiro,
Imagama Shizuka,
Nomura Yuka,
Tanizaki Ryohei,
Minami Yosuke,
Hayakawa Fumihiko,
Ito Yoshie,
Katsumi Akira,
Yamamoto Kazuhito,
Emi Nobuhiko,
Kiyoi Hitoshi,
Naoe Tomoki
Publication year - 2010
Publication title -
european journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.904
H-Index - 84
eISSN - 1600-0609
pISSN - 0902-4441
DOI - 10.1111/j.1600-0609.2009.01387.x
Subject(s) - mapk/erk pathway , phosphorylation , imatinib , cancer research , mek inhibitor , chemistry , cell culture , tyrosine kinase , tyrosine kinase inhibitor , microbiology and biotechnology , tyrosine phosphorylation , medicine , biology , receptor , cancer , biochemistry , myeloid leukemia , genetics
Objective: We investigated the mechanism responsible for imatinib (IM) resistance in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph + ALL) cell lines. Methods: We established cell lines from a patient with Ph + ALL at the time of first diagnosis and relapsed phase and designated as NPhA1 and NPhA2, respectively. We also derived IM‐resistant cells, NPhA2/STIR, from NPhA2 under gradually increasing IM concentrations. Results: NPhA1 was sensitive to IM (IC 50 0.05 μ m ) and NPhA2 showed mild IM resistance (IC 50 0.3 μ m ). NPhA2/STIR could be maintained in the presence of 10 μ m IM. Phosphorylation of MEK and ERK was slightly elevated in NPhA2 and significantly elevated in NPhA2/STIR compared to NPhA1 cells. After treatment with IM, phosphorylation of MEK and ERK was not suppressed but rather increased in NPhA2 and NPhA2/STIR. Active RAS was also increased markedly in NPhA2/STIR after IM treatment. The expression of BCL‐2 was increased in NPhA2 compared to NPhA1, but no further increase in NPhA2/STIR. Proliferation of NPhA2/STIR was significantly inhibited by a combination of MEK inhibitor and IM. Analysis of tyrosine phosphorylation status with a protein tyrosine kinase array showed increased phosphorylation of EphB4 in NPhA2/STIR after IM treatment. Although transcription of EphB4 was suppressed in NPhA1 and NPhA2 after IM treatment, it was not suppressed and its ligand, ephrinB2, was increased in NPhA2/STIR. Suppression of EphB4 transcripts by introducing short hairpin RNA into NPhA2/STIR partially restored their sensitivity to IM. Conclusions: These results suggest a new mechanism of IM resistance mediated by the activation of RAS/MAPK pathway and EphB4.