Myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PV) and essential thrombocythemia (ET), and remarkably shortens survival. Although JAK2V617F and CALR allele burden are the main transformation risk factors, inflammation plays a critical role by driving clonal expansion toward end-stage disease. NF-κB is a key mediator of inflammation-induced carcinogenesis. Here, we explored the involvement of miR-146a, a brake in NF-κB signaling, in MPN susceptibility and progression. rs2910164 and rs2431697, that affect miR-146a expression, were analyzed in 967 MPN (320 PV/333 ET/314 MF) patients and 600 controls. We found that rs2431697 TT genotype was associated with MF, particularly with post-PV/ET MF (HR = 1.5; p < 0.05). Among 232 PV/ET patients (follow-up time=8.5 years), 18 (7.8%) progressed to MF, being MF-free-survival shorter for rs2431697 TT than CC + CT patients (p = 0.01). Multivariate analysis identified TT genotype as independent predictor of MF progression. In addition, TT (vs. CC + CT) patients showed increased plasma inflammatory cytokines. Finally, miR-146a-/- mice showed significantly higher Stat3 activity with aging, parallel to the development of the MF-like phenotype. In conclusion, we demonstrated that rs2431697 TT genotype is an early predictor of MF progression independent of the JAK2V617F allele burden. Low levels of miR-146a contribute to the MF phenotype by increasing Stat3 signaling.
MicroRNAs/genetics , Myeloproliferative Disorders/genetics , Primary Myelofibrosis/genetics , Aged , Alleles , Animals , Cytokines/genetics , Disease Progression , Female , Genotype , Humans , Inflammation/genetics , Inflammation/pathology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Mutation/genetics , Myeloproliferative Disorders/pathology , NF-kappa B/genetics , Polycythemia Vera/genetics , Polycythemia Vera/pathology , Signal Transduction/genetics , Thrombocythemia, Essential/genetics , Thrombocythemia, Essential/pathology
Infection-related mortality (IRM) is responsible for a major proportion of all cases of non-relapse mortality (NRM) after allogeneic PBSCT (alloPBSCT). We analyzed 580 consecutive adults who received a first alloPBSCT from an HLA-identical sibling from 1994 to 2008 at a single institution to describe the severe infections and report the incidence, causes and risk factors for IRM and NRM. Both IRM and NRM decreased with time; within the period of 1994-2000, the 2-year incidence of IRM and NRM was 22 and 31%, respectively, vs 11 and 16% within the period of 2001-2008 (P<0.05 for both comparisons). In multivariate analysis, the variables that increased IRM were within the earlier period of 1994-2000 (P<0.01), poor performance status (P<0.01), grade II-IV acute GVHD (P<0.001) and invasive fungal infection (IFI) (P<0.001) or CMV disease (P<0.001) after transplant. With respect to NRM, earlier time period was also identified as a risk factor (P<0.001), as well as IFIs (P<0.001) and CMV disease (P<0.001). The intensity of the conditioning regimen had no effect on IRM and NRM. These results showed a significant reduction in IRM and NRM over a period of 15 years. The development of IFIs and CMV disease continue to have an impact on NRM.
Infections/mortality , Peripheral Blood Stem Cell Transplantation/adverse effects , Adult , Bacteremia/mortality , Graft vs Host Disease/mortality , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Leukemia/mortality , Multivariate Analysis , Mycoses/etiology , Mycoses/mortality , Myelodysplastic Syndromes/mortality , Peripheral Blood Stem Cell Transplantation/mortality , Recurrence , Siblings , Transplantation, Homologous/adverse effects , Virus Diseases/mortality
Toxicity related to autologous PBSC infusion is well known and traditionally attributed to the presence of DMSO as cryoprotectant. But despite DMSO depletion, adverse events continue appearing. We have conducted a retrospective study to determine the incidence of adverse events related to the PBSC infusion in a large series of 144 patients. Adverse effects were observed in 67.36% of patients, although most of them were of grade 1 or 2. The adverse events most frequently reported were allergic reactions, followed by general, gastrointestinal and respiratory symptoms. In the univariate analysis, age (P=0.01), the volume infused (P=0.005), the amount of DMSO (P=0.008), the total nucleated cells (P=0.002), the total number of granulocytes (P=0.000001) and clumping (P=0.000001) were associated with the occurrence of adverse events. In the multivariate analysis, two protective factors, age (P=0.05) and sex (P=0.004), and two risk factors, the number of granulocytes, with a relative risk of 1.18 (95% confidence interval, 1.06-1.31) (P=0.002), and clumping, with an relative risk of 1.94 (95% confidence interval, 1.15-3.29) (P=0.013), were identified. The best cutoff point for the prediction of the occurrence of adverse events, with a sensitivity of 47% and specificity of 89%, was 6.065 x 10(9) granulocytes.
Leukocyte Count , Peripheral Blood Stem Cell Transplantation/adverse effects , Transplantation, Autologous/adverse effects , Adult , Age Factors , Cell Aggregation , Female , Granulocytes , Humans , Leukapheresis , Male , Middle Aged , ROC Curve , Retrospective Studies , Risk Factors , Sex Factors
