title: LASP1 is a novel BCR-ABL substrate and a phosphorylation-dependent binding partner of CRKL in chronic myeloid leukemia.
abstract: Chronic myeloid leukemia (CML) is characterized by a genomic translocation generating a permanently active BCR-ABL oncogene with a complex pattern of atypically tyrosine-phosphorylated proteins that drive the malignant phenotype of CML. Recently, the LIM and SH3 domain protein 1 (LASP1) was identified as a component of a six gene signature that is strongly predictive for disease progression and relapse in CML patients. However, the underlying mechanisms why LASP1 expression correlates with dismal outcome remained unresolved. Here, we identified LASP1 as a novel and overexpressed direct substrate of BCR-ABL in CML. We demonstrate that LASP1 is specifically phosphorylated by BCR-ABL at tyrosine-171 in CML patients, which is abolished by tyrosine kinase inhibitor therapy. Further studies revealed that LASP1 phosphorylation results in an association with CRKL - another specific BCR-ABL substrate and bona fide biomarker for BCR-ABL activity. pLASP1-Y171 binds to non-phosphorylated CRKL at its SH2 domain. Accordingly, the BCR-ABL-mediated pathophysiological hyper-phosphorylation of LASP1 in CML disrupts normal regulation of CRKL and LASP1, which likely has implications on downstream BCR-ABL signaling. Collectively, our results suggest that LASP1 phosphorylation might serve as an additional candidate biomarker for assessment of BCR-ABL activity and provide a first step toward a molecular understanding of LASP1 function in CML.
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany. These authors contributed equally to this work.
authors.forename: Jochen J
authors.initials: JJ
authors.lastname: Frietsch
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University Clinic of Wuerzburg, Wuerzburg, Germany. These authors contributed equally to this work.
authors.forename: Carolin
authors.initials: C
authors.lastname: Kastner
authors.affiliation: INSERM Unit 830, Genetics and Biology of Cancers, Institute Curie Research Center, Paris, France.
authors.forename: Thomas G P
authors.initials: TG
authors.lastname: Grunewald
authors.affiliation: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Hardy
authors.initials: H
authors.lastname: Schweigel
authors.affiliation: Department of Clinical Chemistry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Research Institute Children's Cancer Center and Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nollau
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Ziermann
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Joachim H
authors.initials: JH
authors.lastname: Clement
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: La Rosée
authors.affiliation: Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.affiliation: Institute for Clinical Biochemistry and Pathobiochemistry, University Clinic of Wuerzburg, Wuerzburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Butt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000328:Adult; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C082869:CRKL protein; D003598:Cytoskeletal Proteins; C096353:LASP1 protein, human; D060588:LIM Domain Proteins; D009687:Nuclear Proteins; D016044:Fusion Proteins, bcr-abl