Prognostic value of 25-hydroxy vitamin D in extranodal NK/T cell lymphoma.

25-hydroxy vitamin D [25-(OH)D] is widely used to determine vitamin D status in clinic. The aim of our study was to evaluate the prognostic value of 25-(OH)D in extranodal NK/T cell lymphoma (ENKTL). Ninety-three (93) ENKTL patients with available serum 25-(OH)D values were enrolled in our study. Vitamin D deficiency is defined as a 25-(OH)D below 50 nmol/L (20 ng/ml). Univariate and multivariate regression analyses were performed to determine independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves were plotted, and corresponding areas under the curves (AUC) were calculated to estimate the accuracy of PINK-E (prognostic index of natural killer lymphoma added with Epstein-Barr virus-DNA status) and 25-(OH)D deficiency in ENKTL risk-stratification. Our results suggested that the vitamin D deficiency was an independent inferior prognostic factor for both PFS [hazard ratio (HR), 2.869; 95% confidence interval (CI), 1.540 to 5.346; P = 0.003] and OS (HR, 3.204; 95% CI, 1.559 to 6.583; P = 0.006) in patients with ENKTL. Additionally, we demonstrated that adding 25-(OH)D deficiency to PINK-E score system indeed has a superior prognostic significance than PINK-E alone for PFS [AUC: 0.796 (95% CI: 0.699 to 0.872) vs. 0.759 (95% CI: 0.659 to 0.841), P = 0.020] and OS [AUC: 0.755 (95% CI: 0.655 to 0.838) vs. 0.721 (95% CI: 0.618 to 0.809), P = 0.040]. In conclusion, our study proved that 25-(OH)D deficiency was associated with inferior survival outcome of ENKTL patients.

Circulating low CD4+/CD8+ ratio is associated with poor prognosis in Waldenstrom macroglobulinemia patients.

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma with great heterogeneity, and the data of peripheral blood T-lymphocyte subsets in WM are limited. This study aimed to investigate the clinical correlation and distribution of circulating T-lymphocyte subsets in newly diagnosed WM patients. We retrospectively searched medical records for 86 newly diagnosed WM patients. Comparisons of the absolute CD3+ T-lymphocyte count (ACD3C), CD4+ T-lymphocyte count (ACD4C), CD8+ T-lymphocyte count (ACD8C), and CD4+/CD8+ T-lymphocyte ratio (CD4+/CD8+) as continuous parameters in different groups were calculated. Univariate and multivariate analyses were used to assess prognostic factors for overall survival (OS) and progression-free survival (PFS). Young patients (<65 years) had lower ACD8C levels and a higher CD4+/CD8+ ratio. And the lower level of ß2-microglobulin (<3 mg/L) was associated with a higher CD4+/CD8+ ratio. With a median follow-up of 25 months, the univariate survival analysis showed that CD4+/CD8+ ratio inversion (CD4+/CD8+<1.5) was associated with shorter OS and PFS, and multivariate analysis confirmed that inverted CD4+/CD8+ ratio could be an independent adverse prognostic factor for OS and PFS. Additionally, initial treatment with rituximab or bortezomib significantly improved the PFS and OS of CD4+/CD8+ inversion patients but did not affect normal CD4+/CD8+ patients. We show that low circulating CD4+/CD8+ ratio at diagnosis is an adverse prognostic factor in WM patients and that first-line therapy which included rituximab or bortezomib significantly improved PFS and OS for patients with CD4+/CD8+ ratio less than 1.5.

The prognostic value of 25-hydroxy vitamin D deficiency and its interaction with c-Myc expression in diffuse large B cell lymphoma.

This study investigated the prognostic value of 25-hydroxy vitamin D (25-(OH)D) deficiency and the association between 25-(OH)D deficiency and c-Myc positivity in 208 newly diagnosed diffuse large B cell lymphoma (DLBCL) patients. 25-(OH)D deficiency was defined as serum 25-(OH)D level lower than 52.5 nmol/L. Using cutoff values of 40%, positive tumor cells for c-Myc expression was established. One hundred forty-two patients had 25-(OH)D deficiency and 70 had c-Myc positivity with a median follow-up of 29 months (range, 16 to 49 months) in this cohort. Multivariate Cox regression analysis showed that 25-(OH)D deficiency was an independent prognostic predictor for inferior progression-free survival (PFS) (P = 0.001) and overall survival (OS) (P = 0.006), and c-Myc positivity was an unfavorable prognostic factor for PFS (P = 0.004). In addition, c-Myc positivity was more frequent in patients with 25-(OH)D deficiency (P = 0.027). Moreover, we found that the presence of c-Myc positivity could aggravate the adverse effects of 25-(OH)D deficiency for PFS time (P = 0.0045). 25-(OH)D deficiency together with IPI (IPI-D) improved the prognostic capacity compared with only IPI in predicting the risk of DLBCL which was assessed by the calculation of receiver operator characteristic (ROC) curves and the areas under the curve (AUC). Noteworthy, c-Myc positivity combined with IPI-D was better than IPI-D in predicting PFS time. In summary, 25-(OH)D deficiency was a strong prognostic factor in DLBCL. Further multi-center prospective studies are needed to confirm the results and better understand the underlying mechanisms.

Interim response in diffuse large B cell lymphoma on CT: what is the optimal size reduction (ΔSPD) for predicting outcome?

OBJECTIVES: To investigate whether there was an optimal interim size reduction (iΔSPD) cutoff value that could discriminate diffuse large B cell lymphoma (DLBCL) patients with poor prognosis. METHODS: This retrospective study enrolled 265 newly diagnosed DLBCL patients with baseline and interim (after 3 cycles) contrast-enhanced computed tomographic scan (CECT) available. Two radiologists evaluated CECT images and selected target lesions according to the Lugano Response Criteria. Lymph nodes greater than 15 mm in longest diameter (LDi) and extra-nodal lesions with LDi greater than 10 mm could be chosen as target lesions and used to calculate iΔSPD. A software tool, X-Tile, was used to calculate the optimal iΔSPD cutoff value to differentiate patients with good vs. poor prognosis. Receiver operating characteristic curve analysis, Cox regression analysis, and Kaplan-Meier analyses were further used to validate the optimal cutoff value. RESULTS: The optimal cutoff value of iΔSPD calculated by X-tile was 80%. Compared with 50% and 100%, 80% cutoff value had the intermediate sensitivity and specificity (57.75% and 86.69% for overall survival (OS), 48.98% and 92.22% for progression-free survival (PFS), respectively), but the maximal Youden index (0.4744 for OS, 0.4120 for PFS, respectively) and areas under the curve (0.737 [0.680, 0.789] for OS). Cox regression analysis also revealed that iΔSPD < 80% could independently predict an inferior OS and PFS (both p < 0.001) while neither iΔSPD < 50% nor iΔSPD = 100% could. CONCLUSIONS: iΔSPD with the cutoff value 80% is an independent predictor of PFS and OS for patients with DLBCL. Results suggest that treatment should be modified for patients with iΔSPD < 80%. KEY POINTS: • The aim of interim response assessment is to identify patients whose disease has not responded to or has progressed on induction therapy. • A cutoff value of 80% in size reduction (ΔSPD) is an independent predictor of PFS and OS for DLBCL patients and is better than 50%. • In DLBCL patients with interim ΔSPD < 80%, a change to a more efficient therapy should be considered.

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia.

TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, ß2-microglobulin ≤3.5 mg/L, wild-type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

The impacts of zanubrutinib on immune cells in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.

Ibrutinib, a first-generation Bruton's tyrosine kinase (BTK) inhibitor, could improve immunity of relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) patients. Whether zanubrutinib, a second-generation selective BTK inhibitor, has similar effects as ibrutinib remains to be determined. Dynamics of number and immunophenotype of immune cells during zanubrutinib treatment in 25 R/R CLL/SLL patients were examined by flow cytometry and blood routine tests. The expression intensity of programmed death-1 (PD-1) on total CD4+ (P < .01), total CD8+ (P < .01), and T helper cells (P < .05) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on total CD4+ (P = .010) and regulatory T cells (P < .05) reduced after treatment. There were significant differences in expression intensity of CD19 (P < .01), C-X-C chemokine receptor type 5 (CXCR5) (P < .01), and CD49d (P < .05) on B cells before and after treatment. Downregulation of PD-1 on T cells and CXCR5 and CD19 on B cells were observed in nearly all patients after zanubrutinib treatment. Programmed death-ligand 1 expression downregulated, especially in the female, CLL, normal spleen, normal ß2-macroglobulin (ß2-MG) and abnormal lactate dehydrogenase (LDH) subgroups, and CTLA-4 expression on CD4+ T cells tended to decrease in the male, old, CLL, splenomegaly, abnormal ß2-MG, normal LDH, IGHV-mutated and wild-type tumor protein 53 subgroups after zanubrutinib treatment. These findings suggest that zanubrutinib can regulate immunity primarily by improving T cell exhaustion, inhibiting suppressor cells and disrupting CLL cells migration through downregulation of adhesion/homing receptors. Furthermore, favorable changes in cell number and immunophenotype were preferably observed in patients without adverse prognostic factors.

Tumor Abnormal Protein Level Predicts Disease Response and Progression of Diffuse Large B-Cell Lymphoma in the Rituximab Era.

BACKGROUND: Changes of glycoprotein are hallmarks for various malignancies; however, the prognostic impact in diffuse large B-cell lymphoma (DLBCL) has not been well elucidated. METHODS: Here we used serum tumor abnormal protein (TAP) level, a lectin-based agglutination assay, to investigate the clinical value of circulating glycoprotein level in DLBCL. One hundred and thirty-one newly diagnosed DLBCL patients treated by rituximab combined chemotherapy were retrospectively enrolled, all with data available for TAP level at initial diagnosis. Additionally, TAP levels during and after initial treatments were measured in 97 cases. RESULTS: Our results showed elevated pre-treatment TAP level was significantly associated with shorter progression-free survival (PFS, p = 0.019) and overall survival (OS, p = 0.025), especially in the high-risk subgroups. In the multivariate Cox regression analyses, pre-treatment TAP level was an independent predictive factor for PFS (p = 0.048). Moreover, ≥ 25% decrease of TAP level indicated superior PFS (p = 0.006) and OS (p = 0.024) in patients with elevated TAP levels at diagnosis. In cases which achieved complete or partial remission, TAP levels were significantly reduced during treatment, but not in non-responsive or progressed patients. CONCLUSIONS: TAP level is a strong prognostic tool for predicting disease progression and monitoring individual response for DLBCL in the rituximab era.

Low T3 syndrome as a predictor of poor prognosis in chronic lymphocytic leukemia.

Low triiodothyronine (T3) state is associated with poor prognosis in critical acute and prolonged illness. However, the information on thyroid dysfunction and cancer is limited. The aim of our study was to evaluate the prognostic value of low T3 syndrome in chronic lymphocytic leukemia (CLL). Two hundred and fifty-eight patients with detailed thyroid hormone profile at CLL diagnosis were enrolled. Low T3 syndrome was defined by low free T3 (FT3) level accompanied by normal-to-low free tetraiodothyronine (FT4) and thyroid-stimulating hormone (TSH) levels. A propensity score-matched method was performed to balance the baseline characteristics. Multivariate Cox regression analyses screened the independent prognostic factors related to time-to-first-treatment (TTFT) and cancer-specific survival (CSS). Area under the curve (AUC) assessed the predictive accuracy of CLL-International Prognostic Index (IPI) together with low T3 syndrome. The results showed that 37 (14.34%) patients had low T3 syndrome, which was significantly associated with unfavorable TTFT and CSS in the propensity-matched cohort, and it was an independent prognostic indicator for both TTFT and CSS. Serum FT3 level was positively related to protein metabolism and anemia, and inversely related to inflammatory state. Patients with only low FT3 demonstrated better survival than those with synchronously low FT3 and FT4, while those with synchronously low FT3, FT4 and TSH had the worst clinical outcome. Low T3 syndrome together with CLL-IPI had larger AUCs compared with CLL-IPI alone in TTFT and CSS prediction. In conclusion, low T3 syndrome may be a good candidate for predicting prognosis in future clinical practice of CLL.

Low serum cholesterol levels predict inferior prognosis and improve NCCN-IPI scoring in diffuse large B cell lymphoma.

Low circulating cholesterol concentration is associated with elevated cancer incidence and mortality. However, the association between cholesterol levels and diffuse large B cell lymphoma (DLBCL) remains unknown. The aim of our study was to evaluate the prognostic value of serum lipid profile in DLBCL. Five hundred and fifty enrolled subjects with detailed serum lipid levels at diagnosis of DLBCL were randomly divided into a training set (n = 367) and a validation set (n = 183) (ratio, 2:1). Multivariate Cox regression analyses screened the prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Performances of models were compared using C-index and area under the curve in internal and external validation. The results showed that decreased levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were associated with unfavorable PFS and OS in the rituximab era, and concurrently low HDL-C together with low LDL-C was an independent prognostic indicator for both PFS and OS. Patients achieving complete remission or partial remission after 6-8 circles of chemotherapies had significantly increased cholesterol levels compared to the levels at DLBCL diagnosis, and HDL-C or LDL-C elevations were correlated with better survival. Furthermore, the predictive and discriminatory capacity of the National Comprehensive Cancer Network (NCCN)-International Prognostic Index (IPI) together with low cholesterol levels was superior to NCCN-IPI alone both in the training and validation set. In conclusion, serum cholesterol levels are simple and routinely tested parameters, which may be good candidates for predicting prognosis in the future clinical practice of DLBCL.

NDRG2 mRNA levels and miR-28-5p and miR-650 activity in chronic lymphocytic leukemia.

BACKGROUND: NDRG2 is identified as a tumor suppressor gene in many tumors, and functions in cell proliferation, differentiation and apoptosis. Recent data indicate that NDRG2 expression is up-regulated by TP53. Moreover, proposed mechanisms of NDRG2 inactivation include epigenetic silencing of the NDRG2 promoter and down-regulation by microRNAs (miRNAs). However, few studies have ever been done on the role of NDRG2 and the NDRG2-regulating miRNAs interference in chronic lymphocytic leukemia (CLL). METHODS: NDRG2 and microRNAs mRNA levels in CLL subjects were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The dual-luciferase reporter assay was performed to determine NDRG2-related miRNAs. Low expression of mature exogenous miRNAs in CLL cells was established by transient transfection. NDRG2 protein levels in CLL cells were detected by western blot. In addition, flow cytometry was conducted to examine the apoptosis of CLL cells. RESULTS: Lower expression of NDRG2 was found in the B-cells from 102 CLL patients compared the 40 normal subjects (P < 0.001). Patients with advanced Binet stage (P = 0.001), high lactate dehydrogenase (LDH) level (P = 0.036), un-mutated immunoglobulin heavy chain variable region gene (IGHV) (P = 0.004) and those with p53 aberrations (P < 0.001) had a markedly lower levels of NDRG2 mRNA. This decrease was associated with briefer time-to-treatment (P = 0.001) and poorer survival (P < 0.001). High expression of miR-28-5p and miR-650 was associated with Binet B/C stage (P = 0.044) and IGHV un-mutated (P = 0.011), as well as Binet B/C stage (P = 0.013) and p53 aberrations (P = 0.037), respectively. Inhibition of miR-28-5p or miR-650 could induce more apoptosis in CLL cells with germline TP53. CONCLUSIONS: NDRG2 mRNA levels might be a useful prognostic variable for patients of CLL and up-regulating NDRG2 transcription may be a therapy approach in CLL without p53 aberrations.

Hyperfibrinogenemia is a poor prognostic factor in diffuse large B cell lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphomas worldwide. Previous studies indicated that hyperfibrinogenemia was a poor predictor in various tumors. The purpose of our study was to evaluate the prognostic effect of hyperfibrinogenemia in DLBCL. Data of 228 patients, who were diagnosed with DLBCL in our hospital between May 2009 and February 2016, were analyzed retrospectively. The Kaplan-Meier method and Cox regression were performed to find prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curve and the areas under the curve were used to evaluate the predictive accuracy of predictors. Comparison of characters between groups indicated that patients with high National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI) score (4-8) and advanced stage (III-IV) were more likely to suffer from hyperfibrinogenemia. The Kaplan-Meier method revealed that patients with hyperfibrinogenemia showed inferior PFS (P < 0.001) and OS (P < 0.001) than those without hyperfibrinogenemia. Multivariate analysis showed that hyperfibrinogenemia was an independent prognostic factor associated with poor outcomes (HR = 1.90, 95% CI: 1.15-3.16 for PFS, P = 0.013; HR = 2.65, 95% CI: 1.46-4.79 for OS, P = 0.001). We combined hyperfibrinogenemia and NCCN-IPI to build a new prognostic index (NPI). The NPI was demonstrated to have a superior predictive effect on prognosis (P = 0.0194 for PFS, P = 0.0034 for OS). Hyperfibrinogenemia was demonstrated to be able to predict poor outcome in DLBCL, especially for patients with advanced stage and high NCCN-IPI score. Adding hyperfibrinogenemia to NCCN-IPI could significantly improve the predictive effect of NCCN-IPI.

A higher percentage of cells with 13q deletion predicts worse outcome in Chinese patients with chronic lymphocytic leukemia carrying isolated 13q deletion.

Previous studies showed that, in chronic lymphocytic leukemia (CLL) patients with isolated 13q deletion (13q-), those carrying higher percentage of leukemic cells with 13q- had more aggressive diseases. However, the prognostic value of the percentage of leukemic cells with 13q- in Chinese CLL patients with isolated 13q- remained to be determined. Using interphase fluorescence in situ hybridization (FISH), we identified 82 patients (25.4%) with isolated 13q deletion from a cohort of 323 untreated CLL patients. Among patients with isolated 13q deletion, cases of 13q- cells ≥ 80% (13q-H) had significantly shorter time to first treatment (TTT) than those of < 80% 13q- cells (13q-L) (median 11 vs. 92 months, p = 0.0016). A higher lymphocyte count (p = 0.0650) was associated with 13q-H, while other clinical, immunophenotypic, or molecular features did not differ between patients with 13q-H and 13q-L. Although 13q-H only showed marginal significance in multivariate analysis of TTT (hazards ratio 2.007; 95% confidence interval 0.975-4.129; p = 0.059), it helped refine the risk stratification based on Binet stage or immunoglobulin heavy chain variable gene (IGHV) status. In cases in Binet A or B stage, patients with 13q-H had a significantly shorter TTT (median TTT 18 months vs. undefined, p = 0.0101). And in IGHV mutated patients, 13q-H was also associated with reduced TTT (median TTT 13q-H. 18 months vs. 13q-L undefined, p = 0.0163). In conclusion, the prognosis of CLL patients with isolated 13q deletion was heterogeneous with 13q-H identifying patients with worse outcome.

Low T3 syndrome is a strong prognostic predictor in diffuse large B cell lymphoma.

The aim of this study was to evaluate the prognostic effect of low triiodothyronine (T3) syndrome on patients with diffuse large B cell lymphoma (DLBCL). A hundred and eighty-eight patients with detailed thyroid hormone levels at diagnosis of DLBCL were enrolled. Low T3 syndrome was defined as a low serum free T3 (FT3) level with low or normal serum free tetraiodothyronine (FT4) and thyroid stimulating hormone levels. Multivariate Cox regression analysis was used to screen prognostic factors associated with progression-free survival (PFS) and overall survival (OS). Receiver-operator characteristic curves and the corresponding areas under the curve were calculated to assess the predictive accuracy of International Prognostic Index (IPI) and low T3 syndrome. Twenty-four patients were diagnosed with low T3 syndrome, which was associated with worse PFS and OS in the rituximab era. It was an independent prognostic factor for PFS and OS, especially for those with IPI 0-2, extranodal sites ≤1 and stage III-IV. Synchronously low FT3 and FT4 had poorer survival outcome compared to only low FT3 and adding criterion of low T3 syndrome improved the prognostic capacity of IPI for predicting PFS and OS in DLBCL. Low T3 syndrome was found to be a strong prognostic predictor in DLBCL.

Negative prognostic impact of low absolute CD4+ T cell counts in peripheral blood in mantle cell lymphoma.

Tumor microenvironment and host immunity are closely related to outcome in patients with mantle cell lymphoma (MCL). However, few researchers have focused on the prognostic value of peripheral blood lymphocyte subsets counts. The purpose of this study was to investigate the prognostic value of lymphocyte subsets and absolute monocyte counts. Sixty-eight patients were analyzed retrospectively. Absolute CD4+ T cell counts (ACD4C), CD8+ T cell counts, nature killer cell counts, and CD4/CD8 ratios were assessed by peripheral blood flow cytometry and correlated with clinical parameters and long-term outcomes. The median follow-up for all patients was 21 months and the median survival time was 44 months. The overall survival (OS) rate at 1, 3, and 5 years was 80%, 51%, and 41%, respectively. In our cohort, high absolute monocyte count, and low ACD4C and CD4/CD8 ratio were associated with unfavorable OS (P = 0.029, P = 0.027, and P = 0.045, respectively) by univariate analysis. Multivariate analysis indicated that low ACD4C was a significant predictor of unfavorable OS (P = 0.004) independent of the simplified MCL International Prognostic Index (P = 0.048) in patients treated with or without rituximab (P = 0.011). Low CD4+ T cell counts proved to be a significant predictor of unfavorable OS in patients with MCL.

MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL.

A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. The MDM2 SNP309 genotypes in 173 CLL patients and 260 healthy controls were detected by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method, which was confirmed by direct DNA sequencing. Compared with the T/T genotype, the SNP309 G/G genotype instead of T/G heterozygote was associated with a significantly increased risk of CLL (OR = 2.84; 95% CI 1.61-5.03; p < 0.001). Age at onset of CLL was similar irrespective of MDM2 status. MDM2 mRNA expression within CLL of G/G genotype was significantly higher than that in T/G (p = 0.009) and T/T genotypes (p < 0.001). Excluding patients with p53 deletions or mutations enhanced the significance of the findings (G/G vs. T/T, p < 0.001; G/G vs. T/G p = 0.001), which prompted us to study the role of the polymorphism in p53 wild-type individuals. In the p53 wild-type groups, survival analysis showed that the patients with MDM2 SNP309 G/G and T/G genotypes both had significantly shorter treatment-free survival (TFS) than SNP309 T/T genotype. Notably, univariate and multivariate analyses showed that MDM2 SNP309 genotypes were associated with TFS. These data show that MDM2 309G polymorphisms contribute to the risk of developing CLL. The unfavorable MDM2 SNP309 G/G genotype was associated with an increase of MDM2 mRNA expression. MDM2 SNP309 was found to be associated with TFS in p53 wild-type Chinese CLL populations.

Downregulated Dicer expression predicts poor prognosis in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Alterations in microRNAs (miRNAs) expression have been proposed to play a role in CLL pathogenesis. Dicer and Drosha are the main regulators of miRNA biogenesis, and deregulation of their expression has been indicated as a possible cause of miRNA alterations observed in various cancers. To investigate the role of Dicer and Drosha in CLL, we assessed the expression of Dicer and Drosha and their correlation with other prognostic factors, including Binet stages, immunoglobulin heavy chain variable gene (IGHV) mutation status, TP53 mutation status, ZAP-70 protein and CD38 expression level in 165 CLL patients by using real-time polymerase chain reaction methods. Patients with unmutated IGHV genes had significantly lower expression of Dicer than patients with IGHV mutations. The lower expression level of Dicer was also significantly associated with higher level of CD38 and ZAP-70, and more aggressive Binet stage. We also analyzed Dicer expression in different cytogenetic subgroups. Lower Dicer level was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22.3) in contrast to higher level in good risk cytogenetics (deletion in 13q14 as the sole abnormality). Furthermore, the lower expression of Dicer in CLL shows a strong association with shorter overall survival (OS) (P = 0.0046) as well as with reduced treatment free survival (TFS) (P = 0.0006). By contrast, no differences in the expression of Drosha among these groups of patients were observed. Our data suggest that Dicer expression may play an important role in the progression and prognosis of CLL.