The Unfolded Protein Response Is a Determinant of Disease Actvity in Waldenstrom's Macroglobulinemia (WM).

Abstract

The unfolded protein response (UPR) maintains the quality of newly synthesized secretory and transmembrane proteins such as immunoglobulins in the endoplasmic reticulum (ER) of eukaryotic cells. The most proximal sensors of the UPR are the ATF6, IRE1a-Xbp1, and PERK proteins. Bip, an ER stress-induced pro-survival molecular chaperone, controls the trafficking of Atf6 and is considered as an indicator of the onset of the UPR. EDEM, downstream of Xbp1 splicing, regulates the extraction of misfolded proteins into the cytosol for proteasome-mediated destruction. Ultimately, the initially cytoprotective UPR triggers an apoptotic cascade if ER stress is not corrected. We studied the UPR stress system in patients with Waldenstrom's Macroglobulinemia (WM), a B-cell disorder characterized by excess secretion of IgM. As part of these efforts, we examined the UPR genes Bip-Atf6, Ire1a-Xbp1, Perk, as well as genes downstream of the UPR pathway including Xbp1 spliced-Edem, eIF2a and Gadd34 using semi-quantitative PCR analysis of CD19+ selected bone marrow lymphoplasmacytic cells (LPC) from 46 patients with the consensus panel diagnosis of WM. We found that UPR gene expression was highly heterogeneous with 16 (35%) patients expressing all genes, whilst 11 patients (24%) expressed only Xbp1 and Edem. Among patients expressing all UPR genes, median serum IgM (p=0.025) and B2M (p=0.05) levels, as well as bone marrow involvement (p=0.06) were higher, with levels of Bip showing greatest correlation to serum IgM and B2M levels, and BM involvement (p=0.01). These results confirm that UPR gene expression is related to disease activity in WM, and suggest a particular role for Bip as a prognostic factor in this disease.