Hyaluronan and proteoglycan link protein 1 (HAPLN1) activates bortezomib-resistant NF-κB 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

doi:10.1074/jbc.ra117.000667

Abstract

Nuclear factor-κB (NF-κB) 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-κB in MM cells. However, we previously reported that a significant fraction of freshly isolated MM cells harbor bortezomib-resistant NF-κB 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-κB pathway in MM cells. We found that this pathway involves bortezomib-resistant degradation of the inhibitor of NF-κB (IκBα), 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-κB activation and thereby promotes bortezomib resistance in MM cells.

Highlights

IntroductionϪ domains, respectively, detected smaller fragments of 20 –25 kDa in 9 of 15 patient BM plasma samples (patients 4, 5, 8 –10, and 12–15) (Fig. 7E)
Ϫ domains, respectively, detected smaller fragments of 20 –25 kDa in 9 of 15 patient BM plasma samples (Fig. 7E)
Domains, respectively, detected smaller fragments of 20 –25 kDa in 9 of 15 patient BM plasma samples (Fig. 7E). This suggests that these smaller species in patient BM samples are HAPLN1 fragments containing the PTR1/2 domains but not the IG domain

Summary

Introduction

Ϫ domains, respectively, detected smaller fragments of 20 –25 kDa in 9 of 15 patient BM plasma samples (patients 4, 5, 8 –10, and 12–15) (Fig. 7E). This suggests that these smaller species in patient BM samples are HAPLN1 fragments containing the PTR1/2 domains but not the IG domain. Our results indicate that HAPLN1 is (i) variably produced by BMSCs, (ii) present in patient BM plasma in both larger forms (ϳ40 – 44 kDa) containing all three domains and smaller forms (20 –25 kDa) containing PTR1/2 domains but lacking the IG domain, and (iii) potentially associated with progressive disease

Results

Discussion

Conclusion