Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type (IgM-MGUS) and Waldenstrom's macroglobulinemia

We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of IgA and IgG paraproteins in MGUS and multiple myeloma (MM). To determine the frequency of paratarg-7 as a paraprotein target in IgM-MGUS and Waldenstrom ́s macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant paratarg-7 by ELISA. The specificity of the paraprotein-mediated reaction was demonstrated by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgMMGUS) of 161 (11%) patients reacted with paratarg-7. Isoelectric focusing and phosphatase treatment revealed that paratarg-7 was hyperphosphorylated (pP-7) in all patients with an antiparatarg-7 specific IgM paraproteins tested. Since only 4/200 (2%) of healthy controls were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio= 6.2; p=0.001) for developing IgM-MGUS/MW. Family analyses revealed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgMMGUS/WM is the second neoplasia associated with pP-7 carrier state. The dominant inheritance of pP-7 explains cases of familial IgM-MGUS/WM and enables the identification of family members at increased risk. Funding Förderverein Krebsforschung Saar-Pfalz-Mosel e.V., HOMFOR and Wilhelm SanderStiftung. For personal use only. on November 12, 2017. by guest www.bloodjournal.org From