Back to Search
Start Over
BCR-ABL-independent and RAS / MAPK pathway-dependent form of imatinib resistance in Ph-positive acute lymphoblastic leukemia cell line with activation of EphB4.
- Source :
-
European journal of haematology [Eur J Haematol] 2010 Mar; Vol. 84 (3), pp. 229-38. Date of Electronic Publication: 2009 Nov 28. - Publication Year :
- 2010
-
Abstract
- Objective: We investigated the mechanism responsible for imatinib (IM) resistance in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) cell lines.<br />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.<br />Results: NPhA1 was sensitive to IM (IC(50) 0.05 microm) and NPhA2 showed mild IM resistance (IC(50) 0.3 microm). NPhA2/STIR could be maintained in the presence of 10 microm 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.<br />Conclusions: These results suggest a new mechanism of IM resistance mediated by the activation of RAS/MAPK pathway and EphB4.
- Subjects :
- Benzamides
Cell Line, Tumor drug effects
Cell Line, Tumor enzymology
Enzyme Activation
Enzyme Induction
Ephrin-B2 genetics
Ephrin-B2 physiology
Female
Humans
Imatinib Mesylate
MAP Kinase Signaling System physiology
Middle Aged
Neoplasm Proteins antagonists & inhibitors
Neoplasm Proteins genetics
Phosphorylation drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology
Protein Processing, Post-Translational drug effects
RNA, Small Interfering pharmacology
Receptor, EphB4 antagonists & inhibitors
Receptor, EphB4 genetics
Recurrence
Drug Resistance, Neoplasm physiology
Fusion Proteins, bcr-abl antagonists & inhibitors
Neoplasm Proteins physiology
Piperazines pharmacology
Precursor Cell Lymphoblastic Leukemia-Lymphoma enzymology
Protein Kinase Inhibitors pharmacology
Pyrimidines pharmacology
Receptor, EphB4 physiology
ras Proteins physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1600-0609
- Volume :
- 84
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- European journal of haematology
- Publication Type :
- Academic Journal
- Accession number :
- 20002159
- Full Text :
- https://doi.org/10.1111/j.1600-0609.2009.01387.x