Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia

Hidetsugu Kawai; Hiromichi Matsushita; Rikio Suzuki; Yin Sheng; Jun Lu; Hideyuki Matsuzawa; Takashi Yahata; Mitsuyo Tsuma-Kaneko; Hideo Tsukamoto; Hiroshi Kawada; Yoshiaki Ogawa; Kiyoshi Ando

doi:10.1016/j.leukres.2014.08.015

Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia

Leuk Res. 2014 Dec;38(12):1451-9. doi: 10.1016/j.leukres.2014.08.015. Epub 2014 Aug 30.

Authors

Affiliations

¹ Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
² Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Laboratory Medicine, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan. Electronic address: hmatsu@is.icc.u-tokai.ac.jp.
³ Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
⁴ Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
⁵ Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
⁶ Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan; Medical Research Institute, Tokai University, Isehara, Kanagawa, Japan. Electronic address: andok@keyaki.cc.u-tokai.ac.jp.

PMID: 25217890
DOI: 10.1016/j.leukres.2014.08.015

Abstract

We analyzed the function of a SEPT9-ABL1 fusion identified in a case of T-prolymphocytic leukemia with tyrosine kinase inhibitor (TKI) resistance. Five isoforms with different N-termini, including SEPT9a-ABL1, SEPT9b-ABL1, SEPT9d-ABL1, SEPT9e-ABL1 and SEPT9f-ABL1, were detected in the leukemic cells. All isoforms except SEPT9d-ABL1 are localized in the cytoplasm, undergo autophosphorylation and phosphorylate the downstream targets, STAT-5 and Crkl, and provided IL-3-independence and in vivo invasiveness to 32D cells. Additionally, these SEPT9-ABL1 isoforms were resistant to TKIs in vitro and in vivo, in comparison to BCR-ABL1. These findings demonstrated that SEPT9-ABL1 had oncogenic activity and conferred resistance to TKIs.

Keywords: ABL1 fusion gene; SEPT9-ABL1; Tyrosine kinase inhibitors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
Animals
Drug Resistance, Neoplasm*
HEK293 Cells
Humans
Leukemia, Prolymphocytic, T-Cell / drug therapy
Leukemia, Prolymphocytic, T-Cell / enzymology*
Leukemia, Prolymphocytic, T-Cell / genetics
Mice
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Oncogene Proteins, Fusion / antagonists & inhibitors
Oncogene Proteins, Fusion / genetics
Oncogene Proteins, Fusion / metabolism*
Phosphorylation / drug effects
Protein Isoforms / genetics
Protein Isoforms / metabolism
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-abl / antagonists & inhibitors
Proto-Oncogene Proteins c-abl / genetics
Proto-Oncogene Proteins c-abl / metabolism*
STAT5 Transcription Factor / genetics
STAT5 Transcription Factor / metabolism
Septins / antagonists & inhibitors
Septins / genetics
Septins / metabolism*

Substances

Adaptor Proteins, Signal Transducing
CRKL protein
Nuclear Proteins
Oncogene Proteins, Fusion
Protein Isoforms
Protein Kinase Inhibitors
STAT5 Transcription Factor
Proto-Oncogene Proteins c-abl
SEPTIN9 protein, human
Septins