nitrophenols and Waldenstrom-Macroglobulinemia

Topics: Antibodies, Bacterial; Antigens; Blood Proteins; Electrolytes; Erythrocytes; Humans; Immunoglobulins; Ligands; Lipoproteins; Multiple Myeloma; Nitrophenols; Paraproteinemias; Peripheral Nerves; Phospholipids; Polysaccharides; Rheumatoid Factor; Waldenstrom Macroglobulinemia

Waldenström macroglobulinemia (WM) is a proliferative disorder of IgM-secreting, lymphoplasmacytoid cells that inhabit the lymph nodes and bone marrow. The disease carries a high prevalence of activating mutations in MyD88 (91%) and CXCR4 (28%). Because signaling through these pathways leads to Bcl-xL induction, we examined Bcl-2 family expression in WM patients and cell lines. Unlike other B-lymphocyte-derived malignancies, which become dependent on expression of anti-apoptotic proteins to counter expression of pro-apoptotic proteins, WM samples expressed both pro- and anti-apoptotic Bcl-2 proteins at low levels similar to their normal B-cell and plasma cell counterparts. Three WM cell lines expressed pro-apoptotic Bcl-2 family members Bim or Bax and Bak at low levels, which determined their sensitivity to inducers of intrinsic apoptosis. In two cell lines, miR-155 upregulation, which is common in WM, was responsible for the inhibition of FOXO3a and Bim expression. Both antagonizing miR-155 to induce Bim and proteasome inhibition increased the sensitivity to ABT-737 in these lines indicating a lowering of the apoptotic threshold. In this manner, treatments that increase pro-apoptotic protein expression increase the efficacy of agents treated in combination in addition to direct killing.

Topics: Apoptosis; Apoptosis Regulatory Proteins; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; Bcl-2-Like Protein 11; Biphenyl Compounds; Bortezomib; Cell Line, Tumor; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression Regulation, Neoplastic; Humans; Membrane Proteins; MicroRNAs; Multiple Myeloma; Nitrophenols; Piperazines; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Waldenstrom Macroglobulinemia

The modification of tryptophan residues in monoclonal immunoglobulin M (IgM) by 2-hydroxy-5-nitrobenzyl bromide (RK) was studied at pH 2.0-2.85 and 7.0 and a RK to tryptophan molar ratio (K) from 1 to 40. At pH 2.85, the number of RK residues bound to IgM (N) in account to one HL-fragments does not exceed 10 (the HL-fragment of IgM contains 14 tryptophan residues); the plot of N vs K reaches a plateau at K greater than 20. When the pH is lowered to approximately 2, N rises to approximately 15, but the plateau is not reached. At pH 7.0, the modified IgM with N greater than 1 gives a sediment, while the product with N approximately equal to 1 remains in solution. Evidently, the latter contains the most accessible tryptophan residue (calculated per one HL-fragment). This residue was found to be one of the three residues localized in the C mu 2-domain and the adjoining N-terminal part. The possibility of multiple modification of tryptophan residues during the RK interaction with IgM in acid medium at high values of K is discussed.

Topics: 2-Hydroxy-5-nitrobenzyl Bromide; Amino Acid Sequence; Antibodies, Monoclonal; Humans; Hydrogen-Ion Concentration; Immunoglobulin M; Nitrophenols; Tryptophan; Waldenstrom Macroglobulinemia

Topics: Antibody Specificity; Binding Sites, Antibody; Erythrocytes; Haptens; Hemagglutination Tests; Heparin; Humans; Hypergammaglobulinemia; Immunodiffusion; Immunoglobulin G; Immunoglobulin kappa-Chains; Immunoglobulin M; Immunoglobulins; Multiple Myeloma; Nitrophenols; Paraproteinemias; Phospholipids; Polysaccharides; Waldenstrom Macroglobulinemia

Topics: Antibodies, Anti-Idiotypic; Antigen-Antibody Reactions; Arthritis, Rheumatoid; DNA; Hemagglutination Inhibition Tests; Humans; Immunoglobulin G; Immunoglobulin M; Macroglobulins; Nitrophenols; Nucleic Acid Denaturation; Rheumatoid Factor; Waldenstrom Macroglobulinemia