A Novel Prognostic Scoring Model for Myelodysplastic Syndrome Patients With SF3B1 Mutation.

The outcomes of myelodysplastic syndrome (MDS) patients with SF3B1 mutation, despite identified as a favorable prognostic biomarker, are variable. To comprehend the heterogeneity in clinical characteristics and outcomes, we reviewed 140 MDS patients with SF3B1 mutation in Zhejiang province of China. Seventy-three (52.1%) patients diagnosed as MDS with ring sideroblasts (MDS-RS) following the 2016 World Health Organization (WHO) classification and 118 (84.3%) patients belonged to lower risk following the revised International Prognostic Scoring System (IPSS-R). Although clonal hematopoiesis-associated mutations containing TET2, ASXL1 and DNMT3A were the most frequent co-mutant genes in these patients, RUNX1, EZH2, NF1 and KRAS/NRAS mutations had significant effects on overall survival (OS). Based on that we developed a risk scoring model as IPSS-R×0.4+RUNX1×1.1+EZH2×0.6+RAS×0.9+NF1×1.6. Patients were categorized into two subgroups: low-risk (L-R, score <= 1.4) group and high risk (H-R, score > 1.4) group. The 3-year OS for the L-R and H-R groups was 91.88% (95% CI, 83.27%-100%) and 38.14% (95% CI, 24.08%-60.40%), respectively (P<0.001). This proposed model distinctly outperformed the widely used IPSS-R. In summary, we constructed and validated a personalized prediction model of MDS patients with SF3B1 mutation that can better predict the survival of these patients.

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling.

OBJECTIVE: To investigate the role of Helicobacter pylori (HP) on the regulation of NF-κB/IL-17 signaling, mechanisms underlying apoptosis in human megakaryocyte cell lines Dami. METHODS: Firstly, the mouse model of immune thrombocytopenia (ITP) was established. Then, the mice were subjected to gastric perfusion with HP. Next, the changes in platelet and bone marrow megakaryocyte classification were assessed in each group. Human megakaryocyte Dami cells were treated with HP in vitro for 3, 6, or 9 h; and the rates of apoptosis in each group were then evaluated with flow cytometry. Fluorescent quantitative PCR and Western blotting were implemented for assessing the expression of Bcl-2 and Bax, which are related to apoptosis, and p65, which is associated with the NF-κB pathway. The expression of these proteins was also evaluated after treatment with PDTC, an inhibitor of the NF-κB pathway inhibitor. RESULTS: In vivo, exogenous administration of HP was found to increase the optical density value for the anti-HP antibody in HP-infected BALB/c mice. Meanwhile, the platelet counts in the HP-infected ITP mice model were significantly reduced compared with non-infected ITP mice. In vitro, the apoptotic rate of Dami cells increased gradually with the prolongation of the exposure to HP; the most noticeable change was at 6 h, and there was a significant difference between 0 h and 6 h. The expression of Bax, p-p65, and IL-17 also increased progressively with the prolongation HP exposure, while the expression of anti-apoptotic Bcl-2 protein decreased gradually, especially at 6 h, and the expression of total p65 did not change significantly compared with baseline. Anecdotally, these effects were reversed by the application of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling. CONCLUSION: HP can promote platelet destruction in ITP mice, and the underlying mechanisms may be related to accelerating apoptosis of megakaryocytes by the activation of the NF-κB/IL-17 pathway.

Prognostic factors on graft-versus-host disease-free and relapse-free survival after allogeneic hematopoietic stem cell transplantation for adults with acute leukemia.

The cure of acute leukemia by allogeneic hematopoietic stem cell transplantation (allo-HSCT) is closely linked to major complications leading to adverse outcomes, including graft-versus-host disease (GVHD), disease relapse and death. This study retrospectively investigated a consecutive series of 312 adult patients with acute leukemia receiving allo-HSCT by using a novel concept of GVHD-free/relapse-free survival (GRFS), and further evaluated the impact of clinical factors on GRFS. Results indicated that the 1- and 2-year GRFS were 54.8% and 51.5%, respectively. In multivariable analysis, recipient age >35years (HR 1.676; p=0.006), diagnosis of acute lymphoblastic leukemia (HR 1.653; p=0.027) and acute biphenotypic leukemia (HR 2.175; p=0.010), advanced disease (HR 2.702; p<0.001), and donor age >35 years (HR 1.622; p=0.008) were significantly associated with inferior GRFS post-HSCT. GRFS of haploidentical-related donor transplant was comparable to that of matched sibling donor or matched unrelated donor transplant. Furthermore, prophylactic donor lymphocyte infusion (DLI) had an overall beneficial effect on GRFS (HR 0.645, p=0.044). Collectively, with a better understanding of these significant prognostic factors which impacted on GRFS, we can effectively evaluate the risk and probability of real recovery after allo-HSCT, further optimizing the therapeutic avenues for acute leukemia.

Characterization of γδ regulatory T cells from peripheral blood in patients with multiple myeloma.

γδ regulatory T cells are able to inhibit the activation and function of T cells involved in antigen-specific immune responses. This study aimed to investigate the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in patients diagnosed as multiple myeloma (MM). We measured the levels of γδ T cells, the distribution and clonally amplified TCR Vγ and VδT cells in peripheral blood of healthy donors, patients recently diagnosed with MM, and MM patients in remission cohorts. In addition, we evaluated the ability of γδ regulatory T cells to inhibit the proliferation of CD4+CD25- T cells and detected the expression of immunoregulatory-associated molecules. We found that the levels of γδ regulatory T cells from the peripheral blood in patients of MM were significantly higher than those in healthy donors. Comparison of γδT regulatory cells function in MM and healthy donors showed similarly inhibitory effects on the proliferation of T cells. Additionally, TLR8 expression level increased significantly in MM patients compared to healthy donors, while the expression levels of Foxp3, CD25, CTLA4, GITR, GATA3 and Tbet in MM patients and healthy donors showed no significant difference. Taken together, our study reveals the potential role of γδ regulatory T cells in inhibiting anti-tumor immune responses in MM patients.

[Clinical significance of NF-kappaB continual activity and expression of WT1 and MDR1 in acute nonlymphocytic leukemia].

The study was aimed to explore the NF-kappaB continual activity and the expression of WT1 and MDR1 in acute non-lymphocytic leukemia (ANLL) patients, and to investigate if the three factors affect the curative effect of ANLL together as to provide some theoretical basis for finding new measures to improve the curative effect of refractory ANLL. The bone marrow samples of 45 ANLL patients was collected. 45 patients including 20 primary ANLL patients (A group) and 25 refractory ANLL patients. Refractory ANLL patients were divided into 2 sub-groups (B, C groups). The primary patients who was no effect after more than two courses of treatment were taken as group B, and the patients with more than two relapses were taken as group C. At the same time, 15 patients with simple iron deficiency anemia were collected as negative control. The NF-kappaB continual activity was measured by using electrophoretic mobility shift assay (EMSA) and the expressions of WT1, MDR1 were detected by reverse transcriptase polymerase chain reaction (RT-PCR). The results showed that the activity of NF-kappaB and the expressions of WT1, MDR1 were not detected in 15 samples of simply iron deficiency anemia subjects. The NF-kappaB continual activity, the expression levels of WT1 and MDR1 in the refractory group were significantly higher than that in primary group (P<0.001). But the NF-kappaB continual activity, the expression of WT1 gene and MDR1 gene were not significantly different between group B and group C (P>0.05). By assaying the relativity between the them the NF-kappaB continual activity and the expression of WT1 or MDR1 had positive correlation in ANLL patients. It is concluded that the NF-kappaB continual activity, the overexpression of WT1 and MDR1 may be one of the reasons causing poor curative effect in acute non-lymphocytic leukemia. The NF-kappaB continual activity and the expression of WT1, MDR1, all show positive correlation in ANLL patients.

[Renin angiotensin system in bone marrow of patients with aplastic anemia].

Renin-angiotensin system (RAS) has been shown to be involved in the growth, production, proliferation and differentiation of the bone marrow (BM) hematopoietic cells, while aplastic anemia (AA) is a disease in which proliferation ability of the BM hematopoietic cells is damaged with defective hematopoietic microenvironment. To investigated the pathogenesis of AA, the rennin activity, angiotensin I (Ang I) and angiotensin II (Ang II) concentration in peripheral blood and BM of 22 AA patients were detected by radioimmunoassay, 16 nonhematological disease patients with normal blood counts and BM picture were used as control, and the difference between two groups was compared. The results showed that BM Ang II concentration in the AA patients was significantly lower than that in the control (P < 0.01). In nonhematological disease patients, Ang II concentration in BM was significantly higher than that in peripheral blood, the renin activities and Ang I concentrations were not significantly different in the two groups (P > 0.05). In conclusion, the decreased BM Ang II concentration in AA patients may be involved to the pathogenesis of AA.

[Inhibitory effect of daunorubicin enhanced by PDTC on drug-resistant leukemic cells in vitro].

To investigate the chemosensitizing effect of pyrroledithiocarbomate (PDTC) on daunorubicin in drug-resistant leukemic cells in vitro, MTT method was used to observe the changes of the proliferation of intractable leukemia MNC treated with daunorubicin (30 microg/ml) combined with PDTC (25, 50 or 100 micromol/L). The results showed that inhibiting rate of daunorubicin combined with PDTC(25, 50 or 100 micromol/L) on drug-resistant leukemic cells was significantly higher than that of daunorubicin alone (P < 0.05). Among the three different doses of PDTC, the concentration of 50 micromol/L of PDTC inhibited the proliferation of drug-resistant leukemic cells significantly. In conclusion, PDTC can sensitize anti-tumor effect of daunorubicin in vitro. The concentration of 50 micromol/L of PDTC has stronger chemosensitizing effect on daunorubicin than that of the other concentrations of PDTC (25 micromol/L or 100 micromol/L) in vitro.