Abstract
Immunomodulatory drugs (IMiDs) are profoundly active compounds in the treatment of patients with multiple myeloma (MM). However, despite the fact that treatment with IMiDs has dramatically improved survival for patients with MM, the majority of MM patients develop IMiDs resistance over time. We have found that expression of functional cereblon is required for IMiDs′ action. In addition, it has been reported that cells expressing high levels of cereblon are resistant to proteasome inhibitor, implying that patients with high levels of cereblon should be resistant to proteasome inhibitor. If the above conclusions are correct, cereblon could be considered as a biomarker to determine which standard regimens should be used to treat patients with MM. Unfortunately, the conclusions mentioned above have not been clinically confirmed. In order to confirm these conclusions, we have generated three highly specific mouse monoclonal antibodies (mAbs) against full-length human cereblon. These mAbs can be used to do western blot, immunoprecipitation and immunohistochemistry staining. In addition, their epitopes have been precisely determined and the peptides covering their epitopes completely blocked the antibody binding to cereblon in western blot analysis or in immunohistochemistry staining of MM patients′ specimens.
Highlights
Multiple myeloma (MM) is generally thought to be incurable, but remissions may be induced with steroids, chemotherapy or stem cell transplants
Given the fact that CRBN binds to the cytosolic C-terminus of large-conductance Ca2+ activated potassium channel (BKCa) [7,8], the cytosolic C-terminus of a voltage-gated chloride channel-2 (ClC-2) [9], AMP-activated protein kinase (AMPK) [10], proteasome subunit β type-4 (PSMB4) [11], ikaros (IKZF1) and aiolos (IKZF3) [12,13,14,15], homeobox protein MEIS2 [16] and argonaute 2 (AGO2) [17], it is possible that CRBN may recruit these proteins for UPS-mediated degradation
We have found that CRBN expression is required for the anti-myeloma activity of IMiDs [18] and introduction of wild-type or His-tagged CRBN into IMiD-resistant cells increased their sensitivities to IMiD [17]
Summary
Multiple myeloma (MM) is generally thought to be incurable, but remissions may be induced with steroids, chemotherapy or stem cell transplants. Given the fact that CRBN binds to the cytosolic C-terminus of large-conductance Ca2+ activated potassium channel (BKCa) [7,8], the cytosolic C-terminus of a voltage-gated chloride channel-2 (ClC-2) [9], AMP-activated protein kinase (AMPK) [10], proteasome subunit β type-4 (PSMB4) [11], ikaros (IKZF1) and aiolos (IKZF3) [12,13,14,15], homeobox protein MEIS2 [16] and argonaute 2 (AGO2) [17], it is possible that CRBN may recruit these proteins for UPS-mediated degradation It is still not clear why some MM patients are sensitive to IMiDs, whereas others are resistant. These mAbs are highly specific and can be used to do western blot, immunoprecipitation and immunohistochemistry staining
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