Abstract
Chronic myelogenous leukemia (CML) is a clonal malignancy of hematopoietic stem cells featured with the fusion protein kinase BCR-ABL. To elicit the mechanism underlying BCR-ABL stability, we perform a screen against a panel of deubiquitinating enzymes (DUBs) and find that the ubiquitin-specific protease 7 (USP7) drastically stabilizes the BCR-ABL fusion protein. Further studies show that USP7 interacts with BCR-ABL and blocks its polyubiquitination and degradation. Moreover, USP7 knockdown triggers BCR-ABL degradation and suppresses its downstream signaling transduction. In line with this finding, genetic or chemical inhibition of USP7 leads to BCR-ABL protein degradation, suppresses BCR/ABL signaling, and induces CML cell apoptosis. Furthermore, we find the antimalarial artesunate (ART) significantly inhibits USP7/BCR-ABL interaction, thereby promoting BCR-ABL degradation and inducing CML cell death. This study thus identifies USP7 as a putative Dub of BCR-ABL and provides a rationale in targeting USP7/BCR-ABL for the treatment of CML.
Highlights
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative malignancy derived from the hematopoietic stem cells of bone marrow[1]
Because USP25 has been reported as a Dub of BCR-ABL, we compared the activity of ubiquitin-specific protease 7 (USP7) and USP25 towards BCR-ABL protein stability
To find out whether USP7 activity was interfered by USP25, we knocked down USP7 from K562 cells, followed by measuring the expression level of both USP7 and USP25, it turned out the USP7 but not USP25 was downregulated by siUSP7 (Fig. 2F)
Summary
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative malignancy derived from the hematopoietic stem cells of bone marrow[1]. The genetic feature in CML is the formation of Philadelphia (Ph) chromosome by the translocation between Chromosomes 9 and 22, which results in the expression of the BCR-ABL fusion gene (the C terminus of the proto-oncogene kinase ABL juxtaposed to the N terminus of the BCR)[2,3]. The ABL kinase shuttles between the cytoplasm and the nucleus and displays both promotive and suppressive functions in cell proliferation and survival upon the context signals, the BCR-ABL fusion (PI3K)/AKT pathway. BCR-ABL promotes CML cell proliferation, survival and anti-apoptosis[4,5,6]. Imatinib (IM) has been widely used for the treatment of CML patients by selectively inhibiting BCR-ABL8
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