MiR-150 Expression in Chronic Myeloid Leukemia: Relation to Imatinib Response.

OBJECTIVE: To assess the circulating micro-RNA-150 (miR-150) expression in patients with chronic myeloid leukemia (CML) in relation to imatinib response. METHODS: Sixty patients with CML and 20 age- and sex-matched control subjects were enrolled. Circulating miR-150 levels were assessed by quantitative real-time polymerase chain reaction on days 0, 14, and 90 of imatinib therapy for patients and once for control subjects. RESULTS: The baseline miR-150 expression was significantly lower in patients with CML than in control subjects with subsequent elevation at 14 and 90 days after the start of imatinib treatment. Early treatment response (ETR) at 90 days was the main study outcome. The miR-150 expression had a significantly higher level in patients with CML with ETR. On multivariate analysis, miR-150 on day 14 was significantly related to ETR in patients with CML with predictive efficacy (area under the curve = 0.838, 72.9% sensitivity, and 84.2% specificity). CONCLUSION: We found that miR-150 expression on day 14 of imatinib treatment is a useful early predictive candidate for imatinib response in patients with CML.

Circulating miR-146a expression predicts early treatment response to imatinib in adult chronic myeloid leukemia.

This study aimed to investigate the prognostic role of circulating miR-146a in the prediction of early response to imatinib treatment in patients with chronic myeloid leukemia (CML). Sixty patients with CML and 20 healthy controls were recruited in this study. BCR-ABL was assessed by quantitative rt-PCR at days 0 and 90 of imatinib therapy. Circulating miR-146a levels were assessed by quantitative rt-PCR at days 0, 14 and 90 of imatinib therapy for patients and once for controls. At day 90 of treatment, treatment response was achieved in 48 patients (80.0%). Responders had significantly lower baseline Sokal score when compared with non-responders. They also had significantly lower BCR-ABL expression at day 90 of treatment. The circulating miR-146a level was significantly lower in patients with CML than in healthy subjects and showed a significant rise after 14 days of imatinib treatment and an inverse correlation with BCR-ABL expression levels at 90 days. Using multivariate logistic regression analysis, baseline BCR-ABL (%) (OR (95% CI) 1.09 (1.03 to 1.016), p=0.006) and miR-146a at 14 days (OR (95% CI) 0.002 (0.0 to 0.09), p=0.001) were significant predictors of treatment response. Using ROC curve analysis, it was found that miR-146a expression at 14 and 90 days could distinguish responders from non-responders (AUC (95% CI) 0.849 (0.733 to 0.928) and 0.867 (0.755 to 0.941), respectively). This study reported for the first time that measurement of the circulating miR-146a expression at 14 days can predict the early response to imatinib treatment in patients with CML. Thus, this work indicates that miR-146a should be investigated in the setting of treatment response to other tyrosine kinase inhibitors.

Prognostic significance of CEBPA mutations and BAALC expression in acute myeloid leukemia Egyptian patients with normal karyotype.

Cytogenetic aberrations are important prognostic factors in acute myeloid leukemia (AML). However, about 50% of newly diagnosed acute myeloid leukemia (AML) cases have normal karyotype. These patients are very heterogenous with respect to acquired gene mutations and gene expression changes. The identification of these genetic alterations may lead to improved prognostification and generation of novel risk-adapted therapies. The aim of this work was to study the prognostic impact of mutations in the myeloid transcription factor gene CEBPA (for CCAAT/enhancer binding protein-alpha) and expression of the BAALC gene (for brain and acute leukemia, cytoplasmic), a novel gene involved in leukemia, in 38 adults with AML and normal cytogenetics. Screening for mutations of CEBPA gene was assessed using PCR-single-strand conformation polymorphism (PCR-SSCP), and BAALC expression was determined by real-time reverse transcriptase polymerase chain reaction in blood or bone marrow samples. CEBPA mutations were found in 7 (18.4%) of 38 patients, 36.8 % (14 of 38) had low BAALC expression and 63.2 % (24 of 38) had high BAALC expression. Patients with CEBPA mutations had favorable course of their disease. They had higher rate of complete remission (CR) (85.7 % vs 51.6 %; P = 0.108), lower incidence of relapse (0% vs. 41.9%; P = 0.038). Disease free survival (DFS) and overall survival (OS) were significantly longer for patients with CEBPA mutations compared with patients without mutations (mean 13.65 +/- 5.41 vs. 7.32 +/- 4.33 months, P = 0.047; mean 15.32 +/- 6.5 vs 8.5 +/- 3.21 months, P = 0.039; respectively). Compared to low BAALC expressers, high BAALC expressers had lower incidence of CR (50% vs 71.4%; P = 0.171), higher incidence of relapse (50% vs. 14.3%; P = 0.029), and showed significantly shorter DFS (mean 7.5 +/- 2.12 vs. 11.67 +/- 4.6 months, P = 0.038) and inferior overall survival (mean 9.1 +/- 3.52 vs. 13.22 +/- 4.21 months, P = 0.024). On multivariable analysis, wild-type CEBPA as well as high BAALC expression were confirmed as independent risk factors predicting inferior DFS (CEBPA, hazard ratio 0.066, P = 0.001; BAALC, hazard ratio 3.98, P = 0.003) and inferior OS (CEBPA, hazard ratio 0.125, P = 0.002; BAALC, hazard ratio 4.215, P = 0.001). Data obtained in this study suggest that CEBPA mutation status and BAALC expression are important prognostic factors in AML patients with normal cytogenetics and their incorporation into novel risk-adapted therapeutic strategies may improve the currently disappointing cure rate of this group of patients.

Significance of zeta-associated protein (ZAP-70) and CD38 expression in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is a disease with a highly variable clinical course; some patients never need treatment, while others require intensive treatment early after diagnosis. Some new prognostic factors, such as immunoglobulin variable heavy chain (IgVH) mutational status, zeta-associated protein (ZAP-70) and CD38 expression in leukemic cells were introduced to identify attenuated versus progressive types of CLL bearing the potential to facilitate risk-adapted treatment strategies. So, the aim of this work is to evaluate the clinical value of ZAP-70 and CD38 as predictors of disease progression. We assessed the expression of these markers by flowcytometry in 38 patients with CLL and correlated their levels with genetic abnormalities detected by fluorescence in situ hybridization (FISH) and the clinical outcome. We found that 18 patients (47.4 %) were positive for ZAP-70 (> or = 20%) and 16 patients (42.1%) were positive for CD38 (> or = 20%). Positive ZAP-70 and CD38 status were associated with an unfavorable clinical course including high leukocytic count, lymphocytosis, high lactate dehydrogenase (LDH) serum level, advanced disease stage, trisomy 12 and del (11q); negative ZAP-70 and CD38 status were correlated with del (13q). The treatment-free survival time was 30 months for ZAP-70-positive patients and 18 months for ZAP-70-nagative patients (p < 0.01). Combined analysis of ZAP-70 and CD38 yielded discordant results in 10 patients (26.3 %), whereas 16 patients (42.1%) were concordantly negative and 12 patients (31.6%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70+CD38+ was 27 months as compared to 100 months in patients with a ZAP-70(-)CD38(-) status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 40 months. Thus, ZAP-70 and CD38 expression analyses provide complementary prognostic information and allow distinguishing the patients groups with the most favorable prognosis as well as those with the worst. The current findings suggest that both ZAP-70 and CD38 protein expression should be assessed in patients with CLL for the definition of prognostic subgroups.