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We investigate the frequency of the human leukocyte antigen DR15 (HLA-DR15) allele in patients with myelodysplastic syndromes (MDS). We used polymerase chain reaction-sequence-specific primers (PCR-SSP) to detect HLA-DR15 in the peripheral blood of patients with MDS(n = 76) and healthy controls (n = 227). The frequency of HLA-DR15 in MDS patients (40.8%) was significantly higher than in controls (13.7%; P < 0.01). The diagnoses of refractory anemia/refractory anemia with ring sideroblasts (RA/RARS) accounted for 77.4% (24/31) and 62.2% (28/45) of the DR15-positive and the DR15-negative patients, respectively (difference not statistically significant). Although no statistically significant difference was observed, some trends were observed: IPSS low-risk MDS (IPSS score, ≤1) accounted for 80.6% of the DR15-positive patients compared to 64.4% among the DR15-negative patients. However, the difference between the numbers of DR15-positive and DR15-negative patients with chromosomal abnormalities was not statistically significant. Nevertheless, poor risk chromosome abnormalities (according to IPSS), were present in only 1 DR15-positive patient, while such abnormalities were present in 8 DR15-negative patients. In addition, the proportions of DR15-positive and DR15-negative patients with more than 5% blasts in marrow were 19.4% and 31.1%, respectively. Peripheral blood pancytopenia occurred in 51.6% of DR15-positive, and in 40.0% of DR15-negative patients. Although the HLA-DR15 allele appeared to be present more frequently in patients less than 60 years of age, this association was not significant. The frequency of HLA-DR15 was significantly higher in patients with MDS than in healthy controls suggesting the possibility that HLA-DR15 is associated with an enhanced susceptibility to develop MDS. The fact that HLA-DR15 was predominantly noted in patients with RA/RARS and low IPSS scores, suggested that HLA-DR15 might be associated more with bone marrow failure and less with leukemic transformation. clinical/experimental characteristics in HLA-DR15 positive or negative MDS patients Cohort HLA-DR15 positive(n=31) HLA-DR15 negative(n=45) P value RA/RARS(case/%) 24/31(77.4) 28/45(62.2) 0.161 Low risk (IPSS≤1) (case/%) 25/31(80.6) 29/45(64.4) 0.126 Karyotype abnormal(case/%) 13/31(41.9) 18/45(40.0) 0.866 Poor chromosome(case/%) 1/31(3.2) 8/45(17.8) 0.117 Blast>5%(case/%) 6/31(19.4) 14/45(31.1) 0.253 Pancytopenia(case/%) 16/31(51.6) 18/45(40.0) 0.317 Male patients(case/%) 17/31(54.8) 25/45(55.6) 0.951 age( Figure Figure Figure Figure

We investigated the frequency of bone marrow (BM) involvement by nonhematological tumors in unselected BM biopsy samples from 10,112 patients. Plastic embedded BM biopsy sections were retrospectively analyzed, with special focus on Frequency of BM involvement by nonhematological malignancies, the advantage of plastic-embedded BM biopsy specimens over paraffin-embedded samples, Complementarity of marrow biopsy to aspiration smears. the causes of false-negative results when using aspiration smears, and analysis of primary sites of metastatic solid tumors. Overall 101 of the 10112 BM samples showed nonhematological tumor metastases, accounting for 1.0% of all analyzed specimens, which was higher than data reported on the basis of paraffin embedded samples. Of 74 aspiration smears obtained concurrently with the 101 biopsy sections, 55 were also positive for metastatic carcinoma. That is, the detection rate of metastatic tumors based on the aspiration smears was 74.3% relative to the rate observed on biopsy sections. All 101 sections with metastatic tumors showed various degrees of myelofibrosis (including 67cases with severe myelofibrosis [+++]) which was thought to be partly responsible for false negative results on aspiration samples. Primary tumors were documented ante-mortem in 50 of the 101 BM biopsy-positive patients (49.5%). The most frequent primary sites were lung, gastroinyestinal tract, and breast, in good agreement with data in the literature. In conclusion, nonhematological tumor metastases in unselected bone marrow are not exceptional findings. Plastic embedded BM biopsy examination is helpful in detecting unknown metastatic nonhematological malignancies and apparently more sensitive than paraffin embedded BM biopsies. Figure Figure Figure Figure

Objective: To explore polarization of T lymphocyte and its relationship with apoptosis of marrow cells in patients with myelodysplastic syndromes (MDS). Methods: Measurement of Th1, Th2, Tc1, Tc2 subsets of marrows from 35 patients with MDS and 13 normal controls was performed by flow cytometry. INF-γ and TNF-α in the bone marrow serum were tested by ELISA (Enzyme-linked immunosorbent assay). Furthermore, apoptosis index of marrow cells was detected by TUNEL (TdT-mediated dUTP nick end labeling). Correlation among Th1, Th2, Tc1, Tc2 subsets and INF-γ, TNF-α level as well as apoptosis index were analyzed, and relationship between TNF-α, INF-γ level and apoptosis index was also investigated. Results: The percentage of Th1 cells (10.1±1.5%), Tc1 cells (24.2±3.5%) and Tc1/Tc2 ratio (49.7±10.8) was significantly increased in patients with MDS when compared to normal controls (4.0±0.5%, 5.8±0.6% and 13.4±2.7, respectively). Level of INF-γ (57.4±21.9pg/ml) and TNF-α (14.6±3.7pg/ml) in bone marrow serum of patients with MDS was markedly elevated compared to normal controls (0 and 0.3±0.2pg/ml, respectively). An increased apoptosis index of nucleated cells was also observed in patients with MDS (7.2±1.5%) when compared to controls (2.1±0.3%, P Conclusions: Th1/Th2, Tc1/Tc2 in bone marrow of patients with MDS were unbalanced, which were polarized to typeIreaction especially in patients with RCMD subtype and lower-risk group. The increased Th1 cells in marrow may account for apoptosis of nucleated marrow cells in MDS, which may act through proapoptotic cytokines such as INF-γ and TNF-α.

Background Despite the efficacy of decitabine treatment in myelodysplastic syndrome (MDS), no definite predictor of response is known. In this study, we investigated whether the expression levels of human equilibrative nucleoside transporter 1 (hENT1), hENT2, deoxycytidine kinase (DCK) and cytidine deaminase (CDA) genes could predict response to decitabine in MDS. Methods We performed quantitative real-time PCR in marrow mononuclear cells to examine the expression of hENT1, hENT2, DCK, and CDA prior to therapy in 98 MDS patients initially treated with decitabine. Response and overall survival of patients treated with decitabine were analyzed according to gene expression levels. HENT1 knockdown was performed by shRNA in the SKM-1 cell line, and the effect of this on the demethylation ability of decitabine on long interspersed nucleotide element 1 (LINE1) was investigated. Results Patients responding to decitabine presented with significantly higher hENT1 expression levels than non-responders (p = 0.004). Overall response, complete response, and cytogenetic complete response rate in patients with high hENT1 expression (79.4, 41.3, and 43.8 %) were significantly higher than those in patients with low hENT1 expression (48.6, 20.0, and 5.9 %, respectively) (p = 0.004, 0.033, and 0.006, respectively). In higher-risk MDS, patients with high hENT1 expression showed prolonged survival compared with those with low hENT1 expression (22.0 vs 14.0 months; p = 0.027). However, the expression levels of hENT2, DCK, and CDA did not affect response rate. Knockdown of hENT1 in SKM-1 cells weakened the demethylation effect on LINE1 induced by decitabine. Conclusions High expression of hENT1 appears to predict a good response to decitabine and a prolonged survival in higher-risk MDS patients treated with decitabine. HENT1 expression knockdown weakens the demethylation effect of decitabine. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0817-9) contains supplementary material, which is available to authorized users.