Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

IgM plasma cell myeloma (PCM) is a rare subtype of myeloma, and its response to novel therapies has not been fully characterized. We describe clinicopathological features and outcome of 17 patients with IgM PCM (11 men and 6 women) with a median age of 63 years. Patients presented with serum hyperviscosity (77%), bone lesions (71%), anemia (65%), renal dysfunction (53%), and hypercalcemia (35%). Median serum IgM level was 6.4 g/dL (0.7-12.1 g/dL). Bone marrow plasma cells (median, 80%; range, 20%-90%) were frequently of lymphoplasmacytic type (8/17; 47%). Immunophenotypically, the myeloma cells were positive for CD38, CD138, CD20 (5/16; 31%), CD56 (4/16; 25%), and CD117 (2/12; 17%); negative for CD19; and decreased or absent CD27 and CD81 in all cases. Seven (41%) patients had a complex karyotype, and fluorescence in situ hybridization showed CCND1-IGH (13/16; 81%), and deletions of 17p13/TP53 (29%) and 13q14/RB1 (38%). No MYD88 L265P mutation was detected. Most patients (94%) received proteasome inhibitor with or without immunomodulatory drug, 62% of patients required multiple regimens because of refractory disease, and 11 (65%) of 17 patients underwent autologous stem cell transplant (ASCT). The median OS was 67 months. After a median follow-up of 38 months (range, 3-106 months), only 5 patients achieved complete remission, 5 had persistent disease, and 7 died (2 progressed to plasma cell leukemia and 1 to blastic variant). In summary, IgM PCM is highly associated with t(11;14) and lymphoplasmacytic morphology. Patients are refractory to novel therapy and progression to high-risk myeloma is common, suggesting a need for alternative novel therapies.
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PMID:IgM plasma cell myeloma in the era of novel therapy: a clinicopathological study of 17 cases. 3026 52

Prima-1Met (APR-246) was previously shown to be dependent on glutathione inhibition and on ROS induction in cancer cells with mutated or deleted TP53. Because this ROS induction was, at least in part, due to a direct interference with the thioredoxin reductase enzyme, we investigated whether activity of Prima-1Met could be mimicked by auranofin, an inhibitor of the thioredoxin reductase. We thus compared the activity of auranofin and Prima-1Met in 18 myeloma cell lines and in 10 samples from patients with multiple myeloma or plasma cell leukemia. We showed that, similar to Prima-1Met, the activity of auranofin was not dependent on either TP53 status or p53 expression; was inhibited by N-acetyl-L-cysteine, a ROS scavenger; displayed a dramatic synergy with L-buthionine sulfoximine, an irreversible inhibitor of glutathione synthesis; and induced cell death that was not dependent on Bax/Bak expression. These data showed that auranofin and Prima-1Met similarly overcome cell death resistance in myeloma cells due to either p53 deficiency or to mitochondrial dysfunction.
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PMID:Targeting Oxidative Stress With Auranofin or Prima-1Met to Circumvent p53 or Bax/Bak Deficiency in Myeloma Cells. 3089 71


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