Abnormal methylation of the sex-determining region Y-box 17 (SOX17) promoter predicts poor prognosis in myelodysplastic syndrome.

BACKGROUND: The sex-determining region Y-box 17 (SOX17) is a member of the high mobility group (HMG) transcription factor family, which plays critical roles in the regulation of development and stem/precursor cell function. Recent evidence demonstrated that SOX17 acts as a tumor-suppressor gene, at least partly though repression of Wnt pathway activity. METHODS: Here we report that SOX17 methylation was detected in THP-1 and SKM-I cell lines and SOX17 mRNA levels was up-regulated by 5-aza-dC. To clarify the role of SOXI7 in MDS, methylation-specific PCR (MSP) was employed to examine the methylation status of SOX17 in 164 adult de novo MDS patients and 6 normal samples. RESULTS: We found that SOX17 methylation was presented in 58.5% (n = 96) of these patients and none of the normal samples. Methylation was correlated significantly with World Health Organization (WHO) subtypes and international prognostic scoring system (IPSS) risk group. Patients with advanced stages of WHO subtypes (69.6% vs. 44.4%, p = 0.001) and higher risk IPSS subgroups (69.8% vs. 48.8%, p = 0.010) exhibited a significantly higher frequency of SOX17 methylation. Though multivariate analysis indicated that SOX17 methylation status was not the independent factor that impacted overall survival (OS) (HR = 0.097), there were significant differences in marrow blast levels and the IPSS risk subgroups between patients with and without SOX17 methylation. CONCLUSIONS: These findings suggest that the hypermethylation of SOX17 promoter may be one of the early events in the development of MDS and predicts poor prognosis.

Evaluation of reference genes and expression patterns of CONSTANS-LIKE genes in Tetrastigma hemsleyanum under different photoperiods.

CONSTANS-LIKE (COL ) genes are a key signalling molecule that regulates plant growth and development during the photoperiod. Our preliminary experiments showed that the photoperiod greatly influence the formation of Tetrastigma hemsleyanum root tubers. In this study, we examined the oscillation patterns and expression characteristics of COL genes in leaves of T. hemsleyanum under different photoperiod conditions. Six genes were selected as candidate reference genes for further analyses: (1) 18S ribosomal RNA (18S rRNA ); (2) α-tubulin (TUBA ); (3) 30S ribosomal RNA (30S rRNA ); (4) TATA binding protein (TBP ); (5) elongation factor 1α (EF-1α ); and (6) RNA polymerase II (RPII ). The geNorm, NormFinder, and BestKeeper software programs were used to evaluate expression stability. Two ThCOL genes were screened in the T. hemsleyanum transcriptome library, and their expression patterns under different photoperiod conditions were analysed using quantitative reverse transcription PCR. The genes EF-1α , TUBA , and 18S rRNA were used to analyse the expression profiles of CONSTANS genes (ThCOL4 and ThCOL5 ) under different photoperiods. The expression peaks of ThCOL4 and ThCOL5 appeared at different times, demonstrating that their oscillation patterns were influenced by the photoperiod. We speculate that these two ThCOL genes may be involved in different biological processes.

Chromosome abnormalities in diffuse large B-cell lymphomas: analysis of 231 Chinese patients.

Genome instability is a hallmark of cancer. Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma with high levels of chromosomal aberrations. The purpose of this study was to characterize chromosomal aberrations in Chinese DLBCL patients and to compare chromosomal abnormalities between germinal centre B-cell-like (GCB) and non-GCB subgroups. Fluorescence in situ hybridization, G-band cytogenetics and immunohistochemistry were performed in 231 cases of de novo DLBCL. We demonstrated that the rate of abnormal and complex karyotypes was 89.1% (139/156) and 92.8% (129/139), respectively. We found a total of 490 structural chromosomal aberrations, including 96 frequent and recurring structural alterations. Most importantly, we identified several rare or novel chromosomal alterations: eight gains (5, 13, 14q, 17, 19p, 20, 21p, Y), one loss (21) and three recurrent translocations [t(7;15)(q22;q22), t(3;20)(p24;q13.1), t(2;3)(q21;q25)]. Moreover, the frequent recurrent genomic imbalance between GCB and non-GCB subgroups was different. Finally, we discovered two cases of concurrent IGH-BCL6 and MYC rearrangements. The rate of abnormal karyotypes in DLBCL patients of Chinese descent was similar to that of Western countries, but some common karyotypes were different, as were the abnormal karyotypes of GCB and non-GCB subgroups. Our discovery of rare and novel abnormal karyotypes may represent unique chromosomal alterations in Chinese DLBCL patients.

Methylation of Wnt antagonist genes: a useful prognostic marker for myelodysplastic syndrome.

Activation of the Wnt signaling pathway has been implicated in the pathogenesis of many tumors as well as in leukemia. However, its role in myelodysplastic syndrome (MDS) is unknown. In this study, we employed methylation-specific PCR to examine the methylation status of six Wnt antagonist genes in 144 MDS patients and in the MDS cell line SKM-1. We also used real-time PCR to examine the expression of Wnt antagonist genes and Wnt pathway genes in the SKM-1 cell line after treatment with 5-aza-2'-deoxycytidine. We found that methylation of the gene promoters of each of the six genes were observed in MDS patients at the following methylation frequencies: 41 % for sFRP1, 89.6 % for sFRP2, 43.1 % for sFRP4, 50.7 % for sFRP5, 44.4 % for DKK-1, and 69.4 % for DKK-3. In the SKM-1 cell line, the gene promoters sFRP1, sFRP2, sFRP5, DKK-1, and DKK-3 were methylated, while sFRP4 was not methylated. Treatment of the SKM-1 cell line with 5-aza-2'-deoxycytidine induced re-expression of methylated Wnt antagonists and inactivation of the Wnt pathway. Survival analysis showed that methylation status of sFRP1, sFRP4, and sFRP5 was associated with worse survival in MDS and sFRP5 methylation also predicted a high risk of leukemia evolution (P = 0.018). Our results indicate that epigenetic regulation of the Wnt pathway in MDS cell line, and the methylation status of Wnt antagonists predicts prognoses of MDS patients.

Prospective nested case-control study of feature genes related to leukemic evolution of myelodysplastic syndrome.

We established a nested case-control study cohort of myelodysplastic syndrome patients (n = 435). And 41 patients had conditions progressing to leukemia (case group = 41), 342 patients had no leukemic transformation (control group = 342), and 52 patients died. Bone marrow mononuclear cell of the patients in the case group and after the evolution were analyzed for the gene expression microarray test (self-control study), whereas the bone marrow mononuclear cell of the paired patients extracted at diagnosis were analyzed for the gene expression microarray test (case-control study). By incorporating the results of above two studies, we identified the genes related to the transformation of myelodysplastic syndrome to acute leukemia. A total of 958 deregulated genes were identified via bioinformatics analysis. Further analyses identified a subset of six genes that help distinguish between the case and control groups. These genes are TUBB, PSMD1, SLC7A5, ATG3, TUBB2C, and TIMM10. The combined gene expression microarray test and nested case-control study method identified a subset of six genes that help distinguish between the case and control groups. The six genes may play critical roles in the evolution of myelodysplastic syndrome to acute leukemia.

Methylation of the CpG island near SOX7 gene promoter is correlated with the poor prognosis of patients with myelodysplastic syndrome.

Myelodysplastic syndrome (MDS), characterized by the decreased production of blood cells, often progresses to acute myeloid leukemia (AML), a sign of poor prognosis of MDS. In AML, the Wnt/ß-catenin pathway is aberrantly activated, suggesting that the increased pathway activity may be correlated with the development and prognosis of MDS. SOX7 protein, encoded by the sex-determining region Y-box 7 (SOX7) gene, inhibits the activity of the Wnt/ß-catenin pathway. Because the DNA methylation can regulate the transcription of SOX7 gene, we used the methylation-specific PCR to investigate the methylation status of the CpG island in MDS patients to determine the potential correlation of the SOX7 methylation with the development and prognosis of MDS. We found that the CpG island of the SOX7 gene was methylated in 58.1% (97/167) of MDS patients, but not in any healthy control. Furthermore, the percentage of patients with the methylated CpG island of the SOX7 gene was significantly higher in patients at advanced stages of MDS than in the patients at early stages. The increased percentages of this SOX7 methylation were also correlated with age, marrow blast levels, and International Prognostic Scoring System (IPSS) risk. After prognostic analysis, we found that patients with the methylated CpG island of the SOX7 gene had shorter overall survival and cumulative survival than patients with unmethylated CpG island. Our findings suggest that the methylation of the CpG island of the SOX7 gene can be used as a predictive factor for the development and prognosis of MDS patients.

Case-control study of risk factors of myelodysplastic syndromes according to World Health Organization classification in a Chinese population.

Risk factors of mydelodysplastic syndromes (MDS) remain largely unknown. We conducted a hospital-based case-control study consisting of 403 newly diagnosed MDS patients according to World Health Organization classification and 806 individually gender and age-matched patient controls from 27 major hospitals in Shanghai, China, to examine relation of lifestyle, environmental, and occupational factors to risk of MDS. The study showed that all MDS (all subtypes combined) risk factors included anti tuberculosis drugs [odds ratio (OR)(adj) = 3.15; 95% confidence interval (CI) = 1.22-8.12] as an independent risk factor, benzene (OR(adj) = 3.73; 95% CI = 1.32-10.51), hair dye use (OR = 1.46; 95% CI = 1.03-2.07), new building and renovations (OR = 1.69; 95% CI = 1.11-2.00), pesticides (OR = 2.16; 95% CI = 1.22-3.82), and herbicides (OR = 5.33; 95% CI = 1.41-20.10) as relative risk factors. Risk factors of MDS subtype refractory cytopenia with multiple dysplasia (RCMD) were benzene (OR(adj) = 5.99; 95% CI = 1.19-30.16) and gasoline (OR(adj) = 11.44; 95% CI = 1.31-100.03) as independent risk factors, and traditional Chinese medicines (OR = 2.17; 95% CI = 1.15-4.07), pesticides (OR = 2.92; 95% CI = 1.37-6.25), and herbicides (OR = 12.00; 95% CI = 1.44-99.67) as relative risk factors. Smoking tobacco was significantly associated with refractory anemia with excess of blasts (RAEB) (OR(adj) = 2.43; 95% CI = 1.02-5.77). Education is shown as an independent protective factor against all MDS (OR(adj) = 0.90; 95% CI = 0.83-0.99) and RCMD (OR(adj) = 0.89; 95% CI = 0.79-0.99). These findings suggest that multiple modifiable behavioral, environmental, and occupational factors play a role in MDS etiology, and various MDS subtypes may have different susceptibility.

[Incidence of adult aplastic anemia in Shanghai, China].

OBJECTIVE: To survey the incidence of acquired adult aplastic anemia (AA) in Shanghai, China. Meanwhile, we compared it with the previous data from China in 1986 and other countries in order to explore the trends. METHODS: Newly diagnosed AA patients were registered in 6 districts (Jingan, Xuhui, Huangpu, Changning, Putuo, Yangpu) in Shanghai from 2004 to 2006. Then we calculated the crude and age-adjusted incidence of AA according to the population data from Shanghai Statistic Yearbook. RESULTS: There were 38 adult patients with acquired AA. The average crude incidence of AA was 0.33/100 000 from 2004 to 2006. The incidences per 100 000 persons per year were 0.40, 0.14 and 0.64 in 18 - 34, 35 - 59 and ≥ 60 years, respectively. The rate of severe AA was 0.17/100 000. CONCLUSION: The incidence of severe AA has no marked change, but the total rate is a little decreased compared with the data from China in 1986.

Therapy-related acute myeloid leukemia in a primary pulmonary leiomyosarcoma patient with skin metastasis.

Primary pulmonary leiomyosarcoma (LMS) is a very unusual tumor. Although LMS has well-known metastatic potential, cutaneous metastasis is a remarkably uncommon. Exposure to cytotoxic agents could lead to "therapy-related myeloid neoplasm" (t-MN). Starting from 2008, the World Health Organization (WHO) has adopted the term to cover the spectrum of malignant diseases previously known as therapy-related acute myeloid leukemia (t-AML), therapy-related myelodysplastic syndrome (t-MDS) and therapy-related myelodysplastic/myelo- proliferative neoplasm (t-MDS/MPN). We described the onset of t-MDS and progression to t-AML in one case diagnosed as primary pulmonary LMS with cutaneous metastasis. This patient achieved complete remission (CR) after three courses of IA regimen chemotherapy (idarubicin 5 mg/d, d 1-3; cytarabine 100 mg/d, d 1-5) and 1 course of HA chemotherapy regimen (homoharringtonine 3 mg/d, d 1-3; cytarabine 100 mg/d, d 1-7). This case presents the natural course of therapy-related neoplasm and provides therapeutic experience for t-AML.

Cytogenetic features and prognosis analysis in Chinese patients with myelodysplastic syndrome: a multicenter study.

It has been suggested that Asian and Western myelodysplastic syndrome (MDS) patients have different cytogenetic and prognostic features. In this study, we retrospectively analyzed clinical and cytogenetic data from 435 Chinese adult primary MDS patients. In addition, we evaluated the prognostic value of the World Health Organization classification as well as six prognostic scoring systems in these patients. The median follow-up time was 25.1 months (5.5-53.2). Of the 435 patients, 186 (42.8%) had died and 40 (9.2%) had progressed to acute myeloid leukemia. Multivariate analysis identified older age, higher percent of marrow blasts, and poor-risk IPSS cytogenetics as characteristics associated with worse survival and higher risk of leukemia transformation. Low platelets, hemoglobin, and mean corpuscular volume were independent factors associated only with worse survival. Among the 424 patients in whom the results of cytogenetic analyses were available, 164 (38.7%) showed karyotypic abnormalities. Incidence of trisomy 8 was common but sole del(5q) was rare in Chinese MDS patients. For predicting survival, most scoring systems were meaningful for stratifying patients into different subgroups, with the exception of the WPSS scoring system. For predicting leukemia evolution, the Spanish scoring system was most effective. Patients with RAEB-2 showed different prognoses from those with RAEB-1. However, there was no significant difference in prognoses between patients with refractory cytopenia with multilineage dysplasia (RCMD) from RA or RARS. In summary, this analysis indicated the presence of a different cytogenetic pattern as well as prognostic features in Chinese MDS patients.

Mean corpuscular volume predicts prognosis in MDS patients with abnormal karyotypes.

The prognostic value of karyotype in patients with myelodysplastic syndrome (MDS) is generally appreciated. However, the factors that are predictive of prognosis of patients with abnormal karyotypes are not known. In this study, we evaluated the prognostic value of International Prognostic Scoring System (IPSS) and World Health Organization classification-based prognostic scoring system (WPSS) in 164 adult MDS patients with abnormal karyotypes. We also analyzed the prognostic relevance of mean corpuscular volume (MCV) in these patients. We found that both IPSS and WPSS had strong prognostic value in patients with abnormal karyotypes (P < 0.001, P < 0.001). Furthermore, we observed the significant differences in the survival of patients with abnormal karyotypes based on MCV stratification: The median survival of patients with macrocytosis was 31.0 months, significantly longer than the 16.5-month median survival time of patients with MCVs of less than 100 fl (P = 0.001). Multivariate analysis revealed that lower level of hemoglobin (P = 0.012, HR = 6.83), higher level of marrow blasts (P < 0.001, HR = 1.93), complex karyotype (P = 0.001, HR = 3.32), and MCV of less than 100 fl (P = 0.026, HR = 1.75) were independent risk factors that affected the survival of patients with abnormal karyotypes.

[The value of flow cytometry for the differential diagnosis between refractory cytopenia with multiple dysplasia and aplastic anemia].

OBJECTIVE: To evaluate the value of flow cytometry (FCM) for the differential diagnosis between myelodysplasia (MDS) subtype refractory cytopenia with multiple dysplasia (RCMD) and aplastic anemia (AA). METHODS: The flow cytometric data of bone marrow samples from 168 cases of RCMD and 77 cases of AA were analyzed retrospectively in blind, and its results were compared with gold standard to evaluate its diagnosis values. RESULTS: The specificity of abnormal of single immunophenotype in the surface of granulocytes and myeloblasts was high (range 75.3%-100%), but the sensitivity was very low (range 5.4%-50%). In parallel tests, the sensitivity and specificity of the combination of CD34+ cells≥1%, myeloblasts≥3%, abnormal expression of CD117 in granulocytes and loss of CD13 in myeloblasts or increased intensity of CD33 in granulocytes were higher than other combinations. The sensitivity and specificity of above combination were more than 62% and 92%, respectively. In the scoring method, different score was given to 8 markers according to different diagnostic value, which were CD34+ cells≥1%, myeloblasts≥3%, abnormal expression of CD117 in granulocytes, loss of CD13 in myeloblasts, increased intensity of CD33 in granulocytes, loss of CD13 in granulocytes, loss of CD10 in granulocytes, and decreased SSC in granulocytes. The sensitivity and specificity were both high if we defined that the total score≥1.5 was RCMD and the score<1.5 was AA. CONCLUSIONS: The value of abnormal of single immunophenotype for differential diagnosis between RCMD and AA is low. Parallel tests can increase the diagnostic sensitivity obviously and not decrease the specificity. CD34+ cells≥1%, myeloblasts≥3% and abnormal expression of CD117 in granulocytes were the most important markers. The scoring method is precise to distinguish RCMD from AA.

Bone marrow blasts level predicts prognosis in patients with refractory cytopenia with multilineage dysplasia.

OBJECTIVES: Current prognostic models for myelodysplastic syndrome (MDS) do not consider the prognostic value of a bone marrow blast level that is <5%. Exploring the prognostic value of the International Prognostic Scoring System (IPSS) and a marrow blast level that is <5% may lead to better risk-adapted therapeutic strategies. METHODS: According to the World Health Organization classification, most of our patients (65.5%) fell into the new category 'refractory cytopenia with multilineage dysplasia' (RCMD). We evaluated the prognostic value of the IPSS in 435 adult patients with de novo MDS and in the 285 of them that had RCMD in a Chinese population. We also analyzed the prognostic value of bone marrow blast levels in patients with RCMD and in different IPSS risk groups. RESULTS: We found a significant difference in survival times between RCMD patients with a marrow blast level of 3.5% or higher vs. those with a blast level of <3.5%, with median survival times of 23.7 and 40.8 months, respectively. In addition, application of a marrow blast level cutoff of 3.5% in patients with RCMD could identify patients with a lower IPSS risk but with a potentially worse prognosis. Multivariate analysis showed marrow blast level (using 3.5% as the cutoff) to be an independent factor that impacted survival times of patients with RCMD. Furthermore, we also found that IPSS had strong prognostic value in Chinese RCMD population. CONCLUSION: In patients with RCMD, a higher percentage of marrow blasts was associated with a worse prognosis.

Retroperitoneoscopic distal pancreatectomy: a new surgical approach.

INTRODUCTION: The traditional laparoscopic surgery is difficult to deal with the deep lesions of the body and tail of the pancreas, which may damage the visceral organs of the abdominal cavity and cause abdominal adhesion and other related complications. AIM: This paper introduces the operation procedure of retroperitoneoscopy in pancreatic surgery, and evaluates its feasibility in clinical application. MATERIAL AND METHODS: Retrospective analysis was performed on patients with retroperitoneal pancreatectomy in our hospital. The anatomical features of the fascia, surgical plane composition and surgical pathway of the fascia of the retroperitoneoscopic pancreatectomy were observed during the operation, and the surgical safety and feasibility were analyzed. The following parameters were evaluated: operation time, blood loss, pancreatic fistula, postoperative gastro-intestinal recovery, hospital stay. RESULTS: All 3 patients had a smooth operation and no serious complications occurred. During retroperitoneal laparoscopic pancreatectomy, there is a vascularized plane between the posterior fascia of the pancreas and the prerenal fascia, which can avoid injury of the visceral organs and retroperitoneal vessels. The anterior renal fascia should be used as the posterior boundary of the safe separation plane. CONCLUSIONS: The surgical plane based on the anatomy of the fascia and interstitial dissection is the theoretical basis of modern surgery, which is safe, fast and effective. The inter-prerenal fascia plane is the correct and safe anatomical plane of posterior laparoscopic surgery.

Prognostic analysis of refractory anaemia in adult myelodysplastic syndromes.

BACKGROUND: Patients with myelodysplastic syndrome (MDS) display a very diverse pattern. In this study, we investigated prognostic factors and survival rate in adult patients with MDS refractory anaemia (MDS-RA) diagnosed according to French-American-British classification and evaluated the International Prognostic Scoring System (IPSS) for Chinese patients. METHODS: A multi-center study on diagnosis of MDS-RA was conducted to characterize the clinical features of Chinese MDS patients. The morphological criteria for the diagnosis of MDS-RA were first standardized. Clinical data of 307 MDS-RA patients collected from Shanghai, Suzhou and Beijing from 1995 to 2006 were analyzed using Kaplan-Meier curve, log rank and Cox regression model. RESULTS: The median age of 307 MDS-RA cases was 52 years. The frequency of 2 or 3 lineage cytopenias was 85.6%. Abnormal karyotype occurred in 35.7% of 235 patients. There were 165 cases (70.2%) in the good IPSS cytogenetic subgroup, 44 cases (18.7%) intermediate and 26 cases (11.1%) poor. IPSS showed 20 (8.5%) categorized as low risk, 195 cases (83.0%) as intermediate-I risk and 20 cases (8.5%) as intermediate-II risk. The 1-, 2-, 3-, 4- and 5-year survival rates were 90.8%, 85.7%, 82.9%, 74.9% and 71.2% respectively. Fifteen cases (4.9%) transformed to acute myeloid leukaemia (median time 15.9 months, range 3 - 102 months). Lower white blood cell count (< 1.5 x 10(9)/L), platelet count (< 30 x 10(9)/L) and cytogenetic abnormalities were independent prognostic factors by multivariate analysis, but age (= 65 years), IPSS cytogenetic subgroup and IPSS risk subgroup were not independent prognostic factors associated with survival time. CONCLUSIONS: Chinese patients were younger, and had lower incidence of cytogenetic abnormalities, more severe cytopenias but a more favourable prognosis than Western patients. The major prognostic factors were lower white blood cell count, lower platelet count and fewer abnormal karyotypes. The international prognostic scoring system risk group was not an independent prognostic factor for Chinese myelodysplastic syndrome patients with refractory anaemia patients.

[Assessment of the young rat model of visceral hypersensitivity by measuring electrical discharge of external oblique].

OBJECTIVE: To study the value of measuring electrical discharge of external oblique in assessment of young rat model of visceral hypersensitivity. METHODS: Eight-day-old neonatal Sprague-Dawley rats were randomly assigned to two groups: an experimental group and a control group (n=16 each). Rats in the experimental group were subjected to mechanical colorectal irritation daily for 7 consecutive days, while the rats in the control group did not received colorectal irritation treatment. On the 6th week of their lives, the spike amplitude of external oblique were measured to evaluate the bowel sensitivity. RESULTS: When the colorectal distention (CRD) pressure was 30 and 45 mmHg, the 95% confidence interval of the spike amplitude in the experimental group was significantly higher than that in the control group (P<0.01). When the CRD pressure were 60 and 75 mmHg, the 95% confidence interval of the spike amplitude in female rats was significantly higher than that in males (P<0.05). CONCLUSIONS: The electrical discharge of external oblique confirmed that chronic colorectal irritation in neonatal rats can result in a chronic visceral hypersensitivity in the juvenile stage, with gender differences. Electrophysiological assessment is a quantitative test, and can objectively reflect visceral sensibility of pain.

Protein-Based Fiber Materials in Medicine: A Review.

Fibrous materials have garnered much interest in the field of biomedical engineering due to their high surface-area-to-volume ratio, porosity, and tunability. Specifically, in the field of tissue engineering, fiber meshes have been used to create biomimetic nanostructures that allow for cell attachment, migration, and proliferation, to promote tissue regeneration and wound healing, as well as controllable drug delivery. In addition to the properties of conventional, synthetic polymer fibers, fibers made from natural polymers, such as proteins, can exhibit enhanced biocompatibility, bioactivity, and biodegradability. Of these proteins, keratin, collagen, silk, elastin, zein, and soy are some the most common used in fiber fabrication. The specific capabilities of these materials have been shown to vary based on their physical properties, as well as their fabrication method. To date, such fabrication methods include electrospinning, wet/dry jet spinning, dry spinning, centrifugal spinning, solution blowing, self-assembly, phase separation, and drawing. This review serves to provide a basic knowledge of these commonly utilized proteins and methods, as well as the fabricated fibers’ applications in biomedical research.

The TNF-alpha 238A polymorphism is associated with susceptibility to persistent bone marrow dysplasia following chronic exposure to benzene.

Chronic exposure to benzene can result in transient hematotoxicity (benzene poisoning, BP) or persistent bone marrow pathology including dysplasia and/or acute myeloid leukemia. We recently described a persistent bone marrow dysplasia with unique dysplastic and inflammatory features developing in individuals previously exposed to benzene (BID) [Irons RD, Lv L, Gross SA, Ye X, Bao L, Wang XQ, et al. Chronic exposure to benzene results in a unique form of dysplasia. Leuk Res 2005;29:1371-80]. In this study we investigated the association of single nucleotide polymorphisms (SNP) (-863 (C-->A), -857 (C-->T), -308 (G-->A), -238 (G-->A)) in the promoter region of the cytokine, tumor necrosis factor-alpha (TNF-alpha) on the development of BP, persistent BID and de novo myelodysplastic syndrome (MDS) in 394 individuals. Only the -238 (G-->A) polymorphism was significantly associated with the development of BID (odds ratio (OR)=7.4; 95% C.I. 1.23-44.7) and was specific for BID and not de novo MDS or BP. These findings are consistent with a role for inflammation in the development of BID and suggest that cell-specific alterations in TNF-alpha expression may promote clonal selection in the evolution of neoplastic hematopoietic disease.