期刊
FRONTIERS IN ONCOLOGY
卷 12, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2022.904510
关键词
chronic myelogenous leukemia; acute lymphocytic leukemia; philadelphia chromosome; Bcr Abl; tyrosine kinase; imatinib (Gleevec); kinase activity; kinase assay
类别
资金
- University of Verona
- AB Analitica, Padova, Italy
Chronic myeloid leukemia (CML) is caused by the fusion tyrosine kinase BCR::ABL1 produced by t(9;22). However, the direct measurement of BCR::ABL1 kinase activity in chronic phase (CP) CML has never been achieved due to degradation in mature leukocytes. In this study, a method was developed to preserve BCR::ABL1 protein in primary CP-CML samples, allowing for the detection of specific kinase activity using a selective substrate. The results showed that BCR::ABL1 kinase activity was barely detectable in CP-CML compared to Ph+ acute lymphoblastic leukemia samples.
Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the acquisition of t(9;22) generating the fusion tyrosine kinase BCR::ABL1. However, despite the crucial role of this protein in the dysregulation of numerous signal transduction pathways, a direct measure of BCR::ABL1 kinase activity in chronic phase (CP) CML was never accomplished due to intense degradative activity present in mature leukocytes. Therefore, we developed a procedure suitable to preserve BCR::ABL1 protein under non-denaturing, neutral pH conditions in primary, chronic phase (CP)-CML samples. As a result, specific kinase activity was detected utilizing a biotinylated peptide substrate highly selective for c-ABL1. Furthermore, through this approach, BCR::ABL1 kinase activity was barely detectable in CP-CML compared to Ph+ acute lymphoblastic leukemia primary samples, where kinase activity is comparable to those measured in Ph+ cell lines. These in vitro findings provide the first direct measure of BCR::ABL1 kinase activity in primary CP-CML and reveal the presence of a still uncharacterized inhibitory mechanism that maintains BCR::ABL1 in a low activity state in CP-CML despite its overexpression.
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