Frietsch Jochen J, Kastner Carolin, Grunewald Thomas G P, Schweigel Hardy, Nollau Peter, Ziermann Janine, Clement Joachim H, La Rosée Paul, Hochhaus Andreas, Butt Elke
Klinik für Innere Medizin II, Abteilung Hämatologie und internistische Onkologie, Universitätsklinikum Jena, Jena, Germany. These authors contributed equally to this work.
Institute for Clinical Biochemistry and Pathobiochemistry, University Clinic of Wuerzburg, Wuerzburg, Germany. These authors contributed equally to this work.
Oncotarget. 2014 Jul 30;5(14):5257-71. doi: 10.18632/oncotarget.2072.
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.
慢性髓性白血病（CML）的特征是基因组易位，产生一个永久激活的BCR-ABL致癌基因，其具有复杂的非典型酪氨酸磷酸化蛋白模式，驱动CML的恶性表型。最近，LIM和SH3结构域蛋白1（LASP1）被鉴定为一种六基因特征的组成部分，该特征对CML患者的疾病进展和复发具有很强的预测性。然而，LASP1表达与不良预后相关的潜在机制仍未得到解决。在此，我们将LASP1鉴定为CML中BCR-ABL的一种新的过表达直接底物。我们证明，在CML患者中，LASP1在酪氨酸171处被BCR-ABL特异性磷酸化，酪氨酸激酶抑制剂治疗可消除这种磷酸化。进一步的研究表明，LASP1磷酸化导致其与CRKL结合——CRKL是另一种特异性BCR-ABL底物，也是BCR-ABL活性的真正生物标志物。pLASP1-Y171在其SH2结构域与非磷酸化的CRKL结合。因此，BCR-ABL介导的CML中LASP1的病理生理过度磷酸化破坏了CRKL和LASP1的正常调节，这可能对下游BCR-ABL信号传导有影响。总体而言，我们的结果表明，LASP1磷酸化可能作为评估BCR-ABL活性的另一个候选生物标志物，并为从分子层面理解LASP1在CML中的功能迈出了第一步。
