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.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, characterized by clonal expansion of differentiated cells
It is thought that leukemia stem cells (LSC) may not be strictly addicted to BCR‐ABL and to be able to bypass BCR‐ABL signaling via other pathways when treated with TK inhibitors [29]
The identification and inhibition of these pathways implicated in LSC survival, in combination with conventional therapy, is the new therapeutic ambition in CML treatment to overcome imatinib resistance and eradicate minimal residual disease (MRD) in CML [29]
Summary
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease, characterized by clonal expansion of differentiated cells. CRKL is an adaptor protein and the major substrate of BCR‐ABL in CML cells [5]. The phosphorylation status of CRKL has been used as a marker to predict the efficacy of tyrosine kinase inhibitors (TKI; e.g. imatinib and nilotinib) in the treatment of CML patients [6, 7]. In this context, we wondered whether other established physiological ABL kinase substrates are prephosphorylated in leukemia cells. Yeung et al recently identified LASP1 as one out of six signature genes that are highly predictive for CML disease phases, which enable a more accurate prediction of relapse after stem cell transplantation than clinical risk factors alone [9]
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