RESUMEN
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.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inmunoglobulinas/sangre , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Examen de la Médula Ósea , Claritromicina/uso terapéutico , Dexametasona/uso terapéutico , Quimioterapia Combinada , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Lenalidomida , Masculino , Persona de Mediana Edad , Proteínas de Mieloma/análisis , Estudios Prospectivos , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
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.
Asunto(s)
Médula Ósea/patología , Janus Quinasa 2/genética , Linfoma de Células B/genética , Mutación Missense , Proteínas de Neoplasias/genética , Mutación Puntual , Anciano , Anciano de 80 o más Años , Alelos , Sustitución de Aminoácidos , Células de la Médula Ósea/enzimología , Susceptibilidad a Enfermedades , Femenino , Humanos , Janus Quinasa 2/análisis , Leucemia Linfocítica Crónica de Células B , Linfoma de Células B/enzimología , Linfoma de Células B/patología , Linfoma de Células B de la Zona Marginal/enzimología , Linfoma de Células B de la Zona Marginal/genética , Linfoma de Células B de la Zona Marginal/patología , Linfoma de Células B Grandes Difuso/enzimología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/enzimología , Linfoma de Células T/genética , Linfoma de Células T/patología , Masculino , Proteínas de Neoplasias/análisis , Neoplasias Primarias Secundarias , Neoplasias Gástricas/enzimología , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologíaRESUMEN
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.