RESUMEN
BIRC3 is a recurrently mutated gene in chronic lymphocytic leukemia (CLL) but the functional implications of BIRC3 mutations are largely unexplored. Furthermore, little is known about the prognostic impact of BIRC3 mutations in CLL cohorts homogeneously treated with first-line fludarabine, cyclophosphamide, and rituximab (FCR). By immunoblotting analysis, we showed that the non-canonical nuclear factor-κB pathway is active in BIRC3-mutated cell lines and in primary CLL samples, as documented by the stabilization of MAP3K14 and by the nuclear localization of p52. In addition, BIRC3-mutated primary CLL cells are less sensitive to flu-darabine. In order to confirm in patients that BIRC3 mutations confer resistance to fludarabine-based chemoimmunotherapy, a retrospective multicenter cohort of 287 untreated patients receiving first-line FCR was analyzed by targeted next-generation sequencing of 24 recurrently mutated genes in CLL. By univariate analysis adjusted for multiple comparisons BIRC3 mutations identify a poor prognostic subgroup of patients in whom FCR treatment fails (median progression-free survival: 2.2 years, P<0.001) similar to cases harboring TP53 mutations (median progression-free survival: 2.6 years, P<0.0001). BIRC3 mutations maintained an independent association with an increased risk of progression with a hazard ratio of 2.8 (95% confidence interval 1.4-5.6, P=0.004) in multivariate analysis adjusted for TP53 mutation, 17p deletion and IGHV mutation status. If validated, BIRC3 mutations may be used as a new molecular predictor to select high-risk patients for novel frontline therapeutic approaches.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Protocolos de Quimioterapia Combinada Antineoplásica , Proteína 3 que Contiene Repeticiones IAP de Baculovirus , Ciclofosfamida/uso terapéutico , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Mutación , Pronóstico , Estudios Retrospectivos , Rituximab/uso terapéuticoRESUMEN
Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.