RESUMEN
Primary myelofibrosis (PMF) is a clonal myeloproliferative neoplasm driven by canonical gene mutations in JAK2, CALR, or MPL in >80% of the cases. PMF that lacks these canonical alterations is termed triple-negative PMF (TN-PMF). The pathologic and genetic characteristics of TN-PMF compared with those of conventional PMF with canonical driver mutations (DM-PMF) have not been well studied. We aimed to identify clinicopathologic and molecular genetic differences between patients with TN-PMF (n = 56) and DM-PMF (n = 89), all of whom fulfilled the 2016 World Health Organization diagnostic criteria for PMF. Compared with the control group, patients in the TN-PMF group were more likely to have thrombocytopenia and less likely to have organomegaly. The bone marrow in patients with TN-PMF showed fewer granulocytic elements and more frequent dyserythropoiesis. Cytogenetic analysis showed a higher incidence of trisomy 8. Targeted next-generation sequencing revealed a lower frequency of ASXL1 mutations but enrichment of ASXL1/SRSF2 comutations. Our findings demonstrated several clinicopathologic and molecular differences between TN-PMF and DM-PMF. These findings, particularly the observed mutation profile characterized by a higher frequency of ASXL1 and SRSF2 comutation, suggest that at least a subset of TN-PMF may be pathogenetically different from DM-PMF, with potential prognostic implications.
Asunto(s)
Trastornos Mieloproliferativos , Mielofibrosis Primaria , Humanos , Médula Ósea/patología , Mielofibrosis Primaria/genética , Mielofibrosis Primaria/patología , Trastornos Mieloproliferativos/genética , Mutación , Pronóstico , Janus Quinasa 2/genética , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Plasma cell myeloma (PCM) is a neoplasm of terminally differentiated B lymphocytes with molecular heterogeneity. Although therapy-related myeloid neoplasms are common in plasma cell myeloma patients after chemotherapy, transdifferentiation of plasma cell myeloma into myeloid neoplasms has not been reported in literature. Here we report a very rare case of myeloid neoplasm transformed from plasma cell myeloma. CASE PRESENTATION: A 60-year-old man with a history of plasma cell myeloma with IGH-MAF gene rearrangement and RAS/RAF mutations developed multiple soft tissue lesions one year following melphalan-based chemotherapy and autologous stem cell transplant. Morphological and immunohistochemical characterization of the extramedullary disease demonstrated that the tumor cells were derived from the monocyte-macrophage lineage. Next generation sequencing (NGS) studies detected similar clonal aberrations in the diagnostic plasma cell population and post-therapy neoplastic cells, including IGH-MAF rearrangement, multiple genetic mutations in RAS signaling pathway proteins, and loss of tumor suppressor genes. Molecular genetic analysis also revealed unique genomic alterations in the transformed tumor cells, including gain of NF1 and loss of TRAF3. CONCLUSION: To our knowledge, this is the first case of myeloid sarcoma transdifferentiated from plasma cell neoplasm. Our findings in this unique case suggest clonal evolution of plasma cell myeloma to myeloma neoplasm and the potential roles of abnormal RAS/RAF signaling pathway in lineage switch or transdifferentiation.
Asunto(s)
Evolución Clonal/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Mieloma Múltiple/genética , Células Plasmáticas/patología , Transformación Celular Neoplásica , Aberraciones Cromosómicas , Humanos , Masculino , Persona de Mediana Edad , Mieloma Múltiple/diagnóstico , Mieloma Múltiple/patología , Patología Molecular/métodosRESUMEN
Staphylococcus aureus induces inflammation in experimental models through Toll-like receptor 2 (TLR2). The clinical relevance of this observation is debated. We evaluated the relationship between TLR2 R753Q single nucleotide polymorphism (SNP) and S aureus infection of joint prosthesis. Human embryonic kidney 293 (HEK293) cells transfected with wild-type and mutant R753Q TLR2 gene were assessed for response to S aureus peptidoglycan. Real-time polymerase chain reaction and gene sequencing of DNA were performed to assess TLR2 R753Q SNP in 76 patients with S aureus prosthetic joint infection (PJI) and 208 noninfected controls. HEK293 cells expressing wild-type TLR2 gene responded robustly to S aureus peptidoglycan, while cells with mutant R753Q TLR2 gene did not. The prevalence of R753Q SNP was high in S aureus PJI patients (heterozygous in 8%, and homozygous in 22%), although not significantly different from controls (12% and 27%, respectively). The TLR2 variant allele was not significantly associated with the risk or survival free of recurrent PJI S aureus. In conclusion, TLR2 R753Q SNP disabled the cellular response to S aureus peptidoglycan in vitro. However, TLR2 R753Q SNP was not significantly associated with the risk or outcome of PJI due to S aureus in human patients.
Asunto(s)
Prótesis Articulares/efectos adversos , Infecciones Estafilocócicas/etiología , Infecciones Estafilocócicas/inmunología , Staphylococcus aureus , Receptor Toll-Like 2/inmunología , Anciano , Artritis Infecciosa/etiología , Artritis Infecciosa/inmunología , Artritis Infecciosa/microbiología , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Estudios de Asociación Genética , Células HEK293 , Humanos , Prótesis Articulares/microbiología , Masculino , Persona de Mediana Edad , Peptidoglicano/inmunología , Polimorfismo de Nucleótido Simple , Staphylococcus aureus/inmunología , Análisis de Supervivencia , Receptor Toll-Like 2/genéticaRESUMEN
BACKGROUND: Hepatitis C virus (HCV) core and nonstructural (NS) 3 proteins induce inflammation and immunity through a toll-like receptor (TLR) 2-dependent pathway. Individuals with the R753Q single-nucleotide polymorphism (SNP) in the TLR2 gene have increased the risk of allograft failure after liver transplantation for chronic hepatitis C. METHODS: To test the hypothesis that R753Q SNP impairs TLR2 recognition of HCV proteins, a series of in vitro experiments were performed wherein stable clones of wild-type TLR2-deficient human embryonic kidney (HEK) 293 cells and HEK293 cells transfected with wild-type (HEK293-TLR2) or variant TLR2 genes (HEK293-TLR2-R753Q) were stimulated with HCV core and NS3 proteins. Cellular activation was assessed by nuclear factor-kappa B-driven luciferase activity, cytokine secretion, and gene upregulation. RESULTS: Compared with TLR2-deficient HEK293 cells, HEK293-TLR2 cells had marked nuclear factor-kappa B-driven luciferase activity, had modest to marked upregulation in TLR2 signaling-associated genes, and secreted large quantities of interleukin-8 during exposure to HCV core and NS3 proteins. In contrast, HEK293-TLR2-R753Q cells did not respond to stimulation with HCV and behaved similarly like TLR2-deficient HEK293 cells. CONCLUSION: R753Q SNP impairs TLR2-mediated immune recognition of HCV core and NS3 proteins. This biologic defect may account for the predisposition of patients to develop allograft failure after liver transplantation for chronic hepatitis C.
Asunto(s)
Inmunidad Innata , Polimorfismo de Nucleótido Simple , Receptor Toll-Like 2/inmunología , Proteínas del Núcleo Viral/inmunología , Proteínas no Estructurales Virales/inmunología , Línea Celular , Regulación de la Expresión Génica , Genes Reporteros , Supervivencia de Injerto , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/cirugía , Humanos , Inmunidad Innata/genética , Interleucina-8/metabolismo , Trasplante de Hígado , FN-kappa B/genética , FN-kappa B/metabolismo , Regiones Promotoras Genéticas , Receptor Toll-Like 2/genética , Receptor Toll-Like 2/metabolismo , Transfección , Trasplante Homólogo , Proteínas del Núcleo Viral/metabolismo , Proteínas no Estructurales Virales/metabolismoRESUMEN
Toll-like receptor 2 (TLR2) serves as a pattern recognition receptor that signals the presence of cytomegalovirus. Herein, we report that R753Q polymorphism paralyzes TLR2-mediated immune signaling in cells exposed to cytomegalovirus glycoprotein B. This immunologic impairment could serve as a biologic mechanism underlying the association between the TLR2 R753Q polymorphism and cytomegalovirus disease in humans.