Dkk3 levels in patients with myeloproliferative neoplasms

Dickkopf-3 (Dkk3) has been proposed as tumor suppressor gene and a marker for tumor blood vessels and has pro-angiogenic properties. Dkk3 is expressed in platelets and megakaryocytes from healthy controls and patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN). The aim of this study is, to find out whether patients with MPN have higher Dkk3 serum levels than normal controls.; We analyzed Dkk3 serum levels with ELISA in patients with newly diagnosed and untreated MPN, including 10 essential thrombocythemia (ET), 10 polycythemia vera (PV), 10 primary meylofibrosis (PMF) and 10 healthy blood donors and correlated these findings with biological and clinical key data and the JAK2-V617F status. Dkk3 levels were corrected to platelet count, Dkk3c, as patients with MPN have higher platelet counts than controls.; As expected, patients with MPN have higher platelet counts than normal controls. Dkk3 serum levels of patients with MPN (5.4 ± 6.1 ng/ml) showed no significant difference compared to normal controls (4.4 ± 3.8 ng/ml). Regarding Dkk3c, a significant difference to controls was found in PV (8.5 ± 8.7 ng/ml; p=0.04), but not in ET and PMF (5.7 ± 3.8 ng/ml; p=0.07 and 2.7 ± 3.6 ng/ml; p=0.9; respectively. Dkk3c correlated with the JAK2-V617F mutational burden (p=0.014, Rho=0.445).; Dkk3 levels corrected to platelet count showed higher levels in PV than normal controls. Elevated Dkk3c level could possibly correlate to platelet activation in PV patients and increased Dkk3 release. Whether this remains a surrogate marker of platelet release or it contributes to the thrombophilic state through its pro-angiogenic properties remains to be shown

Association of host factors with antibody response to seasonal influenza vaccination in allogeneic hematopoietic stem cell transplant (HSCT) patients

BACKGROUND Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood. METHODS We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison. RESULTS Both regression approaches yield consistent results but regression on titers estimated associations with higher precision. HSCT patients required two vaccine doses to achieve average responses comparable to a single dose in HVs. Pre-vaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range and treatment with calcineurin inhibitors lower the odds of responding. CONCLUSIONS HSCT patients show a highly heterogeneous vaccine response, but overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging to identify additional preventive strategies in the poorly responding groups

Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency toward leukemic transformation. We used targeted next-generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patients and followed clonal evolution and the impact on clinical outcome. Mutations in calreticulin (CALR) were detected using a sensitive allele-specific polymerase chain reaction. We observed somatic mutations in 90% of patients, and 37% carried somatic mutations other than JAK2 V617F and CALR. The presence of 2 or more somatic mutations significantly reduced overall survival and increased the risk of transformation into acute myeloid leukemia. In particular, somatic mutations with loss of heterozygosity in TP53 were strongly associated with leukemic transformation. We used NGS to follow and quantitate somatic mutations in serial samples from MPN patients. Surprisingly, the number of mutations between early and late patient samples did not significantly change, and during a total follow-up of 133 patient years, only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low. Our data show that comprehensive mutational screening at diagnosis and during follow-up has considerable potential to identify patients at high risk of disease progression