Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1

Osamu Tomita; Kazutoshi Iijima; Takeshi Ishibashi; Tomoo Osumi; Kenichiro Kobayashi; Hajime Okita; Masahiro Saito; Tetsuya Mori; Toshiaki Shimizu; Nobutaka Kiyokawa

doi:10.1016/j.leukres.2013.11.017

Sensitivity of SNX2-ABL1 toward tyrosine kinase inhibitors distinct from that of BCR-ABL1

Leuk Res. 2014 Mar;38(3):361-70. doi: 10.1016/j.leukres.2013.11.017. Epub 2013 Dec 1.

Authors

Affiliations

¹ Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
² Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan; Department of Industrial Chemistry, Faculty of Engineering, Tokyo University of Science, Shinjuku-ku, Tokyo, Japan.
³ Division of Pediatric Oncology, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.
⁴ Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan.
⁵ Department of Pediatrics, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo, Japan.
⁶ Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Setagaya-ku, Tokyo, Japan. Electronic address: kiyokawa-n@ncchd.go.jp.

PMID: 24367893
DOI: 10.1016/j.leukres.2013.11.017

Abstract

We introduced SNX2-ABL1, a novel ABL1-related chimeric transcript lacks SH3 and SH2 domains, into murine Ba/F3 cells and compared their function with that of BCR-ABL1. After the expression of SNX2-ABL1 proteins, Ba/F3 cells acquired an ability to proliferate in an IL-3-independent manner. Upon treatment with both imatinib and dasatinib, BCR-ABL1-expressing Ba/F3 cells underwent rapid apoptosis, whereas SNX2-ABL1-expressing Ba/F3 cells showed poorer sensitivity toward these TKIs and could proliferate in the presence of a low dose of dasatinib. Therefore, other TKIs with a more selective effect against this chimeric kinase should be used for the treatment of patients with SNX2-ABL1+ ALL.

Keywords: Acute lymphoblastic leukemia; BCR-ABL1; Phosphorylation; SNX2-ABL1; Tyrosine kinase inhibitor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / drug effects*
B-Lymphocytes / immunology
B-Lymphocytes / pathology
Benzamides / pharmacology
Cell Line
Dasatinib
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm
Fusion Proteins, bcr-abl / genetics*
Fusion Proteins, bcr-abl / immunology
Gene Expression Regulation, Leukemic / drug effects*
Genetic Vectors
Humans
Imatinib Mesylate
Interleukin-3 / pharmacology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / immunology
Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology
Mice
Piperazines / pharmacology
Protein Kinase Inhibitors / pharmacology*
Protein Structure, Tertiary
Pyrimidines / pharmacology
Retroviridae / genetics
Sorting Nexins / genetics*
Sorting Nexins / immunology
Thiazoles / pharmacology
Transfection

Substances

BCR-ABL1 fusion protein, human
Benzamides
Interleukin-3
Piperazines
Protein Kinase Inhibitors
Pyrimidines
SNX2 protein, mouse
Sorting Nexins
Thiazoles
Imatinib Mesylate
Fusion Proteins, bcr-abl
Dasatinib