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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Drug Resistance, Neoplasm*
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HEK293 Cells
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Humans
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Leukemia, Prolymphocytic, T-Cell / drug therapy
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Leukemia, Prolymphocytic, T-Cell / enzymology*
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Leukemia, Prolymphocytic, T-Cell / genetics
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Mice
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Oncogene Proteins, Fusion / antagonists & inhibitors
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phosphorylation / drug effects
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins c-abl / antagonists & inhibitors
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / metabolism*
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STAT5 Transcription Factor / genetics
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STAT5 Transcription Factor / metabolism
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Septins / antagonists & inhibitors
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Septins / genetics
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Septins / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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CRKL protein
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Protein Isoforms
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Protein Kinase Inhibitors
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STAT5 Transcription Factor
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Proto-Oncogene Proteins c-abl
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SEPTIN9 protein, human
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Septins