title: Functional analysis of the SEPT9-ABL1 chimeric fusion gene derived from T-prolymphocytic leukemia.
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.
authors.affiliation: 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.
authors.forename: Hidetsugu
authors.initials: H
authors.lastname: Kawai
authors.affiliation: 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.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Yin
authors.initials: Y
authors.lastname: Sheng
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.affiliation: Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Matsuzawa
authors.affiliation: Research Center for Cancer Stem Cell, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yahata
authors.affiliation: 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.
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Tsuma-Kaneko
authors.affiliation: Support Center for Medical Research and Education, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: 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.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kawada
authors.affiliation: Department of Hematology/Oncology, Tokai University School of Medicine, Isehara, Kanagawa, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ogawa
authors.affiliation: 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.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Ando
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019008:Drug Resistance, Neoplasm; D057809:HEK293 Cells; D006801:Humans; D015461:Leukemia, Prolymphocytic, T-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism; D058112:Septins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D016315:Proto-Oncogene Proteins c-abl; C474315:SEPTIN9 protein, human; D058112:Septins
keywords: ABL1 fusion gene; SEPT9-ABL1; Tyrosine kinase inhibitors