RESUMO
The M-protein is the major reference measure for response in multiple myeloma (MM) and its correct interpretation is key to clinical management. The emergence of oligoclonal banding is recognized as a benign finding in the postautologous stem cell transplantation setting (ASCT) for MM but its significance during non-myeloablative therapy is unknown. In a study of the immunomodulatory combination BiRD, (lenalidomide and dexamethasone with clarithromycin), we frequently detected the emergence of mono- and oligo-clonal immunoglobulins unrelated to the baseline diagnostic M-protein. The new M-proteins seen on serum immunofixation electrophoresis were clearly different in either heavy or light chain component(s) from the original M-spike protein and were termed atypical serum immunofixation patterns (ASIPs). Overall, 24/72 (33%) patients treated with BiRD developed ASIPs. Patients who developed ASIPs compared with patients treated with BiRD without ASIPs, had a significantly greater overall response (100% vs. 85%) and complete response rates (71% vs. 23%). ASIPs were not associated with new clonal plasma cells or other lymphoproliferative processes, and molecular remissions were documented. This is the first time this phenomenon has been seen with regularity in non-myeloablative therapy for MM. Analogous to the ASCT experience, ASIPs do not signal incipient disease progression, but rather herald robust response.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imunoglobulinas/sangue , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Exame de Medula Óssea , Claritromicina/uso terapêutico , Dexametasona/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Lenalidomida , Masculino , Pessoa de Meia-Idade , Proteínas do Mieloma/análise , Estudos Prospectivos , Talidomida/análogos & derivados , Talidomida/uso terapêuticoRESUMO
BACKGROUND/AIMS: The JAK2(V617F) mutation, which has been found in patients with myeloproliferative disorders (MPD), has not yet been evaluated in lymphoproliferative disorders by any adequately sensitive techniques. METHODS: We investigated whether low levels of JAK2(V617F) are present in lymphoid neoplasms using a highly sensitive and highly specific amplification refractory mutation system PCR (ARMS-PCR) assay. RESULTS: While 234 of 237 cases did not carry the JAK2(V617F) allele, it was identified in the bone marrow of 3 B cell lymphoma patients. The mutation was found to be neither associated with the lymphomas per se, nor with any signs, symptoms or laboratory findings of MPD. Moreover, JAK2(V617F) appeared subsequently in the peripheral blood of 2 of the 3 patients. CONCLUSION: These findings suggest that JAK2(V617F) arises in the bone marrow of individuals before clinical manifestation of any myeloid disorders. Presence of JAK2(V617F) in bone marrow might therefore increase the risk of future MPD development, just as monoclonal gammopathy of undetermined significance (MGUS) increases the risk of multiple myeloma. We term this phenomenon 'JAK2(V617F) of undetermined significance' (JMUS). Its clinical significance remains to be determined. To our knowledge, these findings represent the first identification of JAK2(V617F) in the bone marrow of patients without myeloid malignancies.
Assuntos
Medula Óssea/patologia , Janus Quinase 2/genética , Linfoma de Células B/genética , Mutação de Sentido Incorreto , Proteínas de Neoplasias/genética , Mutação Puntual , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Células da Medula Óssea/enzimologia , Suscetibilidade a Doenças , Feminino , Humanos , Janus Quinase 2/análise , Leucemia Linfocítica Crônica de Células B , Linfoma de Células B/enzimologia , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/enzimologia , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Difuso de Grandes Células B/enzimologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma de Células T/enzimologia , Linfoma de Células T/genética , Linfoma de Células T/patologia , Masculino , Proteínas de Neoplasias/análise , Segunda Neoplasia Primária , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologiaRESUMO
The PR (PRDI-BF1-RIZ) domain zinc finger protein 1 (PRDM1) is a transcription repressor with a pivotal role in plasma-cell differentiation. We identified clonal inactivating mutations in PRDM1 in the diffuse large B-cell lymphoma (DLBCL) cell line OCI-Ly3 and in 8 of 35 de novo clinical DLBCL samples. The mutational spectrum consists predominantly (7 cases) of single-nucleotide mutations affecting consensus splice donor sites, some of which are recurrent, that lead to splicing aberrations and premature translation termination. In 2 of these cases, point mutations appear to be caused by RNA editing with G-to-A and U-to-G conversions. Other mutations include frame-shift deletion and chromosomal inversion. Except for one mutant, which may act as a dominant-negative, all mutations are associated with either deletion or silencing of the paired PRDM1 allele. This study identifies PRDM1 inactivation as a recurrent genetic defect in DLBCL cells and establishes PRDM1 as a potential tumor suppressor gene in DLBCL. Moreover, it implies inhibition of terminal differentiation as a pathogenetic pathway in DLBCL, particularly for the activated B-cell-like DLBCL. It also demonstrates for the first time the potential role of RNA editing in lymphomagenesis.
