Inactivation of protein‐phosphatase 2A causing hyperphosphorylation of autoantigenic paraprotein targets in MGUS/MM is due to an exchange of its regulatory subunits

Abstract

Hyperphosphorylated paratarg-7 (pP-7) carrier state is the strongest molecularly defined risk factor for monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM). pP-7 is inherited as autosomal-dominant trait and depending on the ethnic background is found in over one-third of MGUS/MM patients. P-7, which is the antigenic paraprotein target in these patients, is hyperphosphorylated at serine 17 . P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCf and reverted by protein-phosphatase 2A (PP2A). Here we show that dephosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of the PP2A by substitution of the regulatory B55d subunit with B56c3. In lymphoblastoid cell lines from pP-7 carriers, transfection of recombinant B55d or treatment with ceramide led to a partial reconstitution of PP2A activity and dephosphorylation of pP-7 to wtP7. Similar results were observed with other previously reported autoantigenic paraproteins targets. In conclusion, the mechanisms responsible for the defective dephosphorylation and maintaining the hyperphosphorylated state of P-7 and other autoantigenic paraprotein targets have been elucidated, facilitating the identification of the genetic basis underlying this phenomenon which is obviously common in the pathogenesis of MGUS/MM/WM and not restricted to pP-7 cases.

Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor

“…The analyses were performed as described (26). The following antibodies were used: anti-HSP90 (1:2000, antibodies-online), anti-SUMO (1:1000, Biozol), and anti-SENP2 (1:1000, antibodies-online).…”

“…ELISA was performed as described (26), with the modification that anti-HSP90 (antibodies-online) was coated (4°C overnight) onto Nunc MaxiSorp plates (Nalge Nunc International) before the plates were blocked with 1.5% gelatin/PBS.…”

“…LCLs were established by infection of PBMCs with EBV and cultured as described previously (28). Transfections and analyses were performed as described (26).…”

Germline Risk Contribution to Genomic Instability in Multiple Myeloma

“…Additional autoantigenic paraprotein targets were subsequently identified, all of which are hyper-phosphorylated in affected patients (Grass et al, 2011). Hyper-phosphorylation may be the result of de-phosphorylation deficiency based on evidence indicating that de-phosphorylation of pP-7 is defective in pP-7 carriers due to inactivation of protein-phosphatase 2A (PP2A) (Preuss et al, 2014). The studies described above and exciting new research by Dhodapkar’s group (Nair et al, 2018) are consistent with the hypothesis that immune responses to post-translationally modified proteins and lipids play a role in myelomagenesis.…”

Incidence and inheritance of hyperphosphorylated paratarg-7 in patients with Waldenstrom’s macroglobulinaemia in Sweden

“…P-7 hyperphosphorylation can be induced in wild-type P-7 (wtP-7) carriers by PKCf and reverted by protein phosphatase 2A (PP2A). In pP-7 carriers, dephosphorylated pP-7 is defective due to inactivation of the PP2A [13]. The carrier state of pP-7 is inherited in an autosomal dominant fashion and carrier of pP-7 has a higher risk for developing MM, MGUS and WM (MM: odds ratio = 7.9, p ¼ .0001; WM: odds ratio = 6.2, p ¼ .001) [13,14].…”