A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS

Preuss, Klaus‐Dieter; Pfreundschuh, Michael; Ahlgrimm, Manfred; Fadle, Natalie; Regitz, Evi; Murawski, Niels; Grass, Sandra

doi:10.1002/ijc.24427

Cited by 43 publications

(70 citation statements)

References 26 publications

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“…We recently identified paraprotein target 7 (paratarg-7) as the target of up to 37% of paraproteins from monoclonal gammopathies of undetermined significance (MGUS)/multiple myeloma (MM) patients (1)(2)(3). All patients with paratarg-7-specific paraproteins were carriers of a hyperphosphorylated modification of paratarg-7 (pP-7) (4), and the pP-7 carrier state is inherited in an autosomaldominant fashion (4).…”

Section: Introductionmentioning

confidence: 99%

Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor

Preuss¹,

Pfreundschuh²,

Fadle³

et al. 2014

J. Clin. Invest.

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Section: Introductionmentioning

confidence: 99%

Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor

Preuss¹,

Pfreundschuh²,

Fadle³

et al. 2014

J. Clin. Invest.

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“…20 For testing the P-7 specificity of the recombinant B-cell receptor (BCR), the P-7 ELISA was performed according to standard protocols with the use of the expressed and purified recombinant Fab antibodies.…”

Section: P-7 Enzyme-linked Immunoabsorbent Assaymentioning

confidence: 99%

Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenström macroglobulinemia

Grass

Preuss

Wikowicz

et al. 2011

Blood

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We recently described paratarg-7 (P-7), a protein of unknown function, as the target of 15% of immunoglobulin A (IgA) and IgG paraproteins in monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma. To determine the frequency of P-7 as a paraprotein target in IgM-MGUS and Waldenströ m macroglobulinemia (WM), sera from patients with IgM-MGUS/WM were tested for reactivity with recombinant P-7 by enzyme-linked immunoabsorbent assay.The specificity of the paraprotein-mediated reaction was shown by absorption studies and cloning of the respective B-cell receptor. The paraproteins of 18 (9 WM and 9 IgM-MGUS) of 161 patients (11%) reacted with P-7. Isoelectric focusing and phosphatase treatment showed that P-7 was hyperphosphorylated (pP-7) in all patients with an anti-P-7-specific IgM paraprotein tested. Because only 4 of 200 healthy controls (2%) were carriers of pP-7, pP-7 carrier state is associated with a significantly increased risk (odds ratio ‫؍‬ 6.2; P ‫؍‬ .001) for developing IgM-MGUS/MW. Family analyses showed that the pP-7 carrier state is inherited as a dominant trait. After IgA/IgG-MGUS and multiple myeloma, IgM-MGUS/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. (Blood. 2011; 117(10):2918-2923) IntroductionWaldenström macroglobulinemia (WM) is classified as an immunoglobulin M (IgM)-secreting B-cell non-Hodgkin lymphoma characterized primarily by lymphoplasmacytic infiltrates in the bone marrow accompanied by hypersecretion of monoclonal IgM. It corresponds to the lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification. 1 Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor condition commonly preceding multiple myeloma (MM), and IgM-MGUS may precede development of WM. 2 Although age, race, sex, and preexisting IgM-MGUS are recognized risk factors, the cause of WM is largely unknown. Several studies have shown a significantly increased risk of WM after infections with hepatitis B virus, immunodefinciency virus, and rickettsiosis and found an increased risk of WM among persons with a personal history of autoimmune disease. 3 Genetic factors play an important role, with 20% of patients having a familial predisposition. Several studies of multiple affected families have been published, showing familial clustering of LPL and WM. [4][5][6] A recent study showed that family members of patients with MGUS and LPL-WM have a significant higher risk of MGUS/LPL-WM. 7 Environmental influences, chance occurrence, and inherited factors may all contribute to familial clusters. The evidence of somatic immunoglobulin gene mutations in WM indicates a role for antigenic stimulation in the development of WM. [8][9][10] A causal relationship between MGUS/WM and chronic antigenic stimulation has been suggested by the results of several studies. [8][9][10][11][12] Because of the rari...

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“…2,5 Absorption studies using His 6 -tagged P-8 protein or erythrocyte lysates were performed as described before for P-7. 2,5 Similarly, Western blot analyses, isoelectric focusing (IEF), and phosphatase treatment of all paraprotein targets were performed as described before for P-7. 2,5…”

Section: Patients and Controlsmentioning

confidence: 99%

“…2,5 For the P-8 ELISA, recombinant P-8 was used as a coat, and the ELISA was performed according to standard protocols using the paraproteins at a dilution of 1:10 6 .…”

Section: P-7 and P-8 Elisamentioning

confidence: 99%

Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM

Grass

Preuss

Thomé

et al. 2011

Blood

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Paratarg-7 (P-7) is a frequent paraprotein target in monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and Waldenströ m macroglobulinemia. Patients with P-7-specific paraproteins carry a hyperphosphorylated paratarg-7 (pP-7). Because pP-7 carrier state is dominantly inherited, we determined the paraprotein targets in 4 families with familial MGUS/MM. No antigenic target was identified for the paraproteins from 2 members of one family. Paraproteins from affected members of 2 other families targeted P-7, and paraproteins from 4 affected members of a fourth family targeted P-8, which is encoded by the ATG13 gene. P-8 was hyperphosphorylated in the affected family members (pP-8) and pP-8 carrier state is inherited in a dominant fashion. Six additional autoantigenic nonfamilial paraprotein targets were also hyperphosphory- IntroductionUsing a human fetal brain-derived protein macroarray in a modified SEREX 1 approach, we identified paratarg-7 (P-7) as the target of 15% of IgA or IgG paraproteins 2 and 11% of IgM paraproteins. 3 All patients with P-7 specific paraproteins are carriers of a hyperphosphorylated version of the protein (pP-7), and this hyperphosphorylation is inherited in a dominant fashion. 2,4 pP-7 carrier state is associated with an increased risk of developing IgA/IgG monoclonal gammopathy of undetermined significance (MGUS)/multiple myeloma (MM) (odds ratio ϭ 7.9) 2 and IgM-MGUS (odds ratio ϭ 6.5). 3 Because pP-7 is the first molecularly defined risk factor for any hematologic neoplasm known to date, 2,3 we set out to define the antigenic targets of paraproteins from affected members of families with familial MGUS/MM. Methods Patients and controlsThis study was approved by the local ethical review board (Ethikkommission der Ä rztekammer des Saarlandes) and conducted according to the Declaration of Helsinki. Peripheral blood and serum samples from 31 healthy and 10 affected members of 4 families with familial MGUS/MM were collected after obtaining written informed consent. Serum screening on high-density protein arrays, immunoblot analyses, absorption studies, IEF, and phosphatase treatment of paraprotein targetsThese were performed as described before. 2,5 Absorption studies using His 6 -tagged P-8 protein or erythrocyte lysates were performed as described before for P-7. 2,5 Similarly, Western blot analyses, isoelectric focusing (IEF), and phosphatase treatment of all paraprotein targets were performed as described before for P-7. 2,5 P-7 and P-8 ELISAThe ELISA using full-length recombinant P-7 was performed as described by us previously. 2,5 For the P-8 ELISA, recombinant P-8 was used as a coat, and the ELISA was performed according to standard protocols using the paraproteins at a dilution of 1:10 6 . Results and discussionFour families with Ն 2 cases of MGUS/MM were included in this study. No antigenic target was identified for the paraproteins from a brother and a sister of the first family, both affected by MM. Two sisters diagnosed with MGUS in the second famil...

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A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS

Cited by 43 publications

References 26 publications

Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor

Sumoylated HSP90 is a dominantly inherited plasma cell dyscrasias risk factor

Hyperphosphorylated paratarg-7: a new molecularly defined risk factor for monoclonal gammopathy of undetermined significance of the IgM type and Waldenström macroglobulinemia

Paraproteins of familial MGUS/multiple myeloma target family-typical antigens: hyperphosphorylation of autoantigens is a consistent finding in familial and sporadic MGUS/MM

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