Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-B activity and increases drug resistance in multiple myeloma

Mailee Huynh, Chorom Pak, Stephanie Markovina, Natalie S. Callander, Kenneth S. Chng, Shelly M. Wuerzberger-Davis, Debayan D. Bakshi, John A. Kink, Peiman Hematti, Chelsea Hope, Fotis Asimakopoulos, Lixin Rui, Shigeki Miyamoto

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Abstract

Nuclear factor-B (NF-B) is a family of transcription factors that play a key role in cell survival and proliferation in many hematological malignancies, including multiple myeloma (MM). Bortezomib, a proteasome inhibitor used in the management of MM, can inhibit both canonical and noncanonical activation of NF-B in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-B activity. Here, we report that hyaluronan and proteoglycan link protein 1 (HAPLN1) is produced in bone marrow stromal cells from MM patients, is detected in patients’ bone marrow plasma, and can activate an atypical bortezomib-resistant NF-B pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-B (IB), despite efficient bortezomib-mediated inhibition of proteasome activity. Moreover, HAPLN1 can also confer bortezomib-resistant survival of MM cells. We propose that HAPLN1 is a novel pathogenic factor in MM that induces an atypical NF-B activation and thereby promotes bortezomib resistance in MM cells.

Original languageEnglish
Pages (from-to)2452-2465
Number of pages14
JournalJournal of Biological Chemistry
Volume293
Issue number7
DOIs
StatePublished - Feb 16 2018

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    Huynh, M., Pak, C., Markovina, S., Callander, N. S., Chng, K. S., Wuerzberger-Davis, S. M., Bakshi, D. D., Kink, J. A., Hematti, P., Hope, C., Asimakopoulos, F., Rui, L., & Miyamoto, S. (2018). Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-B activity and increases drug resistance in multiple myeloma. Journal of Biological Chemistry, 293(7), 2452-2465. https://doi.org/10.1074/jbc.RA117.000667