Prognostic significance of microRNA 17–92 cluster expression in Egyptian chronic lymphocytic leukemia patients

Abstract Background Abnormal expression patterns of microRNAs (miRs) play an important role in the development and progression of malignancy. Identification of the clinical significance and prognostic value of these small molecules in chronic lymphocytic leukemia (CLL); a disease of heterogeneous biological landscape and clinical course, has always been of tremendous translational value. Aim To evaluate the prognostic value of microRNA17-92 cluster members in Egyptian CLL patients. Methods The expression levels of miR17-92 cluster members were evaluated by qRT-PCR, including miR17, miR18a, miR19a, miR19b-1, miR20a, and miR92a-1. Other investigations included serum LDH, serum β2 microglobulin (β2M), CD38 and ZAP70 expression by flow cytometry, fluorescence in situ hybridization (FISH) for 17p deletion, and imaging studies (computerized tomography (CT) scans of neck, chest, abdomen, and pelvis or PET-CT scans). Results Overexpression of all members of the miRNA17-92 cluster was detected in CLL patients compared to controls (p = < 0.001 for all miRs while p = 0.01 for miR19b-1). A significant positive correlation between Hb and miR17 and a significant negative correlation between Hb and miR19b-1 were observed (p = 0.041, 0.017 respectively). A statistically significant positive correlation between miR19b-1 expression and each of the WBCs and absolute lymphocytic count (ALC) was detected (p = 0.023, 0.022 respectively). Moreover, a statistically significant relation between miR19b-1 expression and advanced Binet stages was also found (p = 0.05). Regarding miR18a, a statistically significant positive correlation with LDH level was found (p = 0.003). We also found a significant positive correlation between miR92a-1 and β2M level (p = 0.005), as well as a significant relation between miR17 and negative CD38 expression (p = 0.034). However, no significant relationships between any of studied miRNA expression levels and 17p deletion or response to treatment were observed. Patients who expressed miR19b-1 were significantly indicated to start therapy at diagnosis (p = 0.05). The overall survival of CLL patients included in our study was 90.2% after 1 year from the time of diagnosis. Patients with high expression of miR19a had better OS than those with low expression (p = 0.04). Conclusions Overexpression of all members of the miR17-92 cluster was detected in Egyptian CLL patients. MiR18a, miR19b-1, and miR92a-1 also have an adverse prognostic value while miR17 can be considered a good prognostic marker. High expression of miR19a is associated with better OS.

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CD72 Expression Patterns in ZAP70 Positive and Negative Chronic Lymphocytic Leukemia: Potential Regulatory Role in BCR Signalling

Blood ◽

10.1182/blood.v112.11.4159.4159 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4159-4159

Author(s):

Francisco P. Careta ◽

Rodrigo A. Panepucci ◽

Daniel M Matos ◽

Rodrigo Proto-Siqueira ◽

Wilson A. Silva-Junior ◽

...

Keyword(s):

B Cells ◽

Chronic Lymphocytic Leukemia ◽

Expression Patterns ◽

Surrogate Marker ◽

Lymphocytic Leukemia ◽

Negative Regulator ◽

Beta Catenin ◽

Cell Surface Glycoprotein ◽

Expression Levels

Abstract Introduction: Absence of mutations in IgVH genes or higher number of ZAP70+ cells (as a surrogate marker) in chronic lymphocytic leukemia (CLL) B-cells defines a patient group with a poorer clinical course. These features relate to the role of BCR signalling in the proliferation and survival of CLL B-cells, and establish a link between these markers and the biology of CLL prognostic subgroups. The identification of additional players in this context may help to better understand the molecular basis of this disease and contribute to develop new therapeutic approaches. A search for genes potentially related to BCR signalling, when comparing mutated and unmutated CLL cases using serial analysis of gene expression, revealed a 4-fold increase of CD72 tags in unmutated samples, a specific B cell surface glycoprotein known to transmit both positive and negative signals in BCR signalling. Objective: This finding lead us to explore the potential role of CD72 on BCR signalling in distinct CLL prognostic subgroups, as defined by ZAP70 expression. Methods: Percentage of ZAP70+ and CD72+ cells were evaluated by flow cytometry on gated CD19+CD5+ cells in 25 CLL samples. Positive cases for ZAP70 and CD72 were defined using a cut-off of 35% and 40% positive cells, respectively. Real time PCR was used to quantify the expression levels of 3 genes related to proliferation and survival, RELB, Beta-Catenin (CTNNB1) and AKT1, on 16 CD19+ enriched (purity > 90%) CLL samples. Results: Samples were classified as 11 ZAP70+ and 14 ZAP70−. Median percentage of CD72+ cells in ZAP70+ was significantly higher than for ZAP70− cases (82% compared to 39%, respectively, P=0.0029). Furthermore, percentages of CD72 and ZAP70 were positively correlated (r=0.5930 and P=0.0009). Interestingly, ZAP70+ cases were restricted to CD72+ cases (n=11, CD72+ZAP70+ [+/+]), whereas six CD72+ cases were ZAP70− (ZAP70−CD72+ [−/+]). Finally, there were 8 cases CD72−ZAP70− [−/−]. No differences among these 3 groups were observed in regard to laboratory parameters (white blood cells, total lymphocytes, lymphocyte percentage, haemoglobin, haematocrit and platelet number). Despite the reduced number of samples analysed (6 +/+, 6 −/− and 4 −/+), transcripts for RELB (P<0.05), CTNNB1 (P<0.05), and AKT1(P=0.057) were expressed at higher levels in ZAP70+CD72+ than in ZAP70−CD72+ samples. Additionally, the transcripts were expressed at higher levels in ZAP70−CD72− than in ZAP70−CD72+ samples, and this difference was statistically significant (P<0.05) for CTNB1 and AKT1, but not for RELB (P=0.054). Conclusion: Our data indicate that higher percentages of ZAP70+ cells are associated with higher expression levels of transcripts related to proliferation and survival of CLL B-cells. In the absence of ZAP70 expression, CD72 may act as a negative regulator of the BCR pathway, as indicated by the lowest levels of transcripts on ZAP70−CD72+ cases.

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Prognostic value of immune checkpoint molecules in breast cancer

Bioscience Reports ◽

10.1042/bsr20201054 ◽

2020 ◽

Vol 40 (7) ◽

Author(s):

Jun Fang ◽

Feng Chen ◽

Dong Liu ◽

Feiying Gu ◽

Zhigang Chen ◽

...

Keyword(s):

Breast Cancer ◽

Immune Checkpoint ◽

Prognostic Value ◽

Immune Therapy ◽

Expression Patterns ◽

Immune Checkpoint Blockade ◽

Checkpoint Blockade ◽

High Expression ◽

Expression Levels ◽

Checkpoint Genes

Abstract Immune checkpoint blockade treatments bring remarkable clinical benefits to fighting several solid malignancies. However, the efficacy of immune checkpoint blockade in breast cancer remains controversial. Several clinical trials of immune checkpoint blockades focused on the effect of CTLA4 and PD1/PDL1 checkpoint inhibitors on breast cancer. Only a small portion of patients benefited from these therapies. Here we systematically investigated the expression of 50 immune checkpoint genes, including ADORA2A, LAG-3, TIM-3, PD1, PDL1, PDL2, CTLA-4, IDO1, B7-H3, B7-H4, CD244, BTLA, TIGIT, CD80, CD86, VISTA, CD28, ICOS, ICOSLG, HVEM, CD160, LIGHT, CD137, CD137L, OX40, CD70, CD27, CD40, CD40LG, LGALS9, GITRL, CEACAM1, CD47, SIRPA, DNAM1, CD155, 2B4, CD48, TMIGD2, HHLA2, BTN2A1, DC-SIGN, BTN2A2, BTN3A1, BTNL3, BTNL9, CD96, TDO, CD200 and CD200R, in different subtypes of breast cancer and assessed their prognostic value. The results showed that the expression patterns of these 50 immune checkpoint genes were distinct in breast cancer. High expression of B7-H3 mRNA was significantly associated with worse overall survival (OS), especially in patients with luminal A and luminal B breast cancer. The mRNA expression levels of TIM-3, ADORA2A, LAG3, CD86, CD80, PD1 and IDO1 had no relationship with OS in breast cancer. High expression levels of CTLA-4 and TIGIT were correlated with favorable prognosis in breast cancer. Interestingly, we observed that B7-H3 expression was negatively correlated with the efficacy of cyclophosphamide (CTX). In summary, our study suggested that B7-H3 has potential prognostic value in breast cancer and is a promising target for immune therapy.

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Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes

Blood ◽

10.1182/blood-2005-04-1483 ◽

2006 ◽

Vol 107 (5) ◽

pp. 2090-2093 ◽

Cited By ~ 39

Author(s):

Dirk Kienle ◽

Axel Benner ◽

Alexander Kröber ◽

Dirk Winkler ◽

Daniel Mertens ◽

...

Keyword(s):

Gene Expression ◽

Chronic Lymphocytic Leukemia ◽

Expression Patterns ◽

Gene Expression Pattern ◽

Cell Receptor ◽

Lymphocytic Leukemia ◽

Expression Of Genes ◽

Vh Genes ◽

Signaling Activation

The mutation status and usage of specific VH genes such as V3-21 and V1-69 are potentially independent pathogenic and prognostic factors in chronic lymphocytic leukemia (CLL). To investigate the role of antigenic stimulation, we analyzed the expression of genes involved in B-cell receptor (BCR) signaling/activation, cell cycle, and apoptosis control in CLL using these specific VH genes compared to VH mutated (VH-MUT) and VH unmutated (VH-UM) CLL not using these VH genes. V3-21 cases showed characteristic expression differences compared to VH-MUT (up: ZAP70 [or ZAP-70]; down: CCND2, P27) and VH-UM (down: PI3K, CCND2, P27, CDK4, BAX) involving several BCR-related genes. Similarly, there was a marked difference between VH unmutated cases using the V1-69 gene and VH-UM (up: FOS; down: BLNK, SYK, CDK4, TP53). Therefore, usage of specific VH genes appears to have a strong influence on the gene expression pattern pointing to antigen recognition and ongoing BCR stimulation as a pathogenic factor in these CLL subgroups.

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The prognostic value of a proliferation-inducing ligand (APRIL) serum levels in treatment-naive patients with chronic lymphocytic leukemia

TURKISH JOURNAL OF MEDICAL SCIENCES ◽

10.3906/sag-2004-282 ◽

2021 ◽

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Prognostic Value ◽

Serum Levels ◽

Lymphocytic Leukemia ◽

Treatment Naïve

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Prognostic Value of Autoantibodies against Erythrocytes and Platelets in Chronic Lymphocytic Leukemia (CLL)

Tumori Journal ◽

10.1177/030089169107700202 ◽

1991 ◽

Vol 77 (2) ◽

pp. 100-104 ◽

Cited By ~ 2

Author(s):

Giulio De Rossi ◽

Lucia Granati ◽

Gabriella Girelli ◽

Giuseppe Gandolo ◽

Paola Perrone ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Prognostic Value ◽

Lymphocytic Leukemia

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PF380 SINGLE CELL ABNORMALITIES ON CLASSIC G-BANDING ANALYSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA: CLINICOBIOLOGICAL FEATURES AND PROGNOSTIC VALUE

HemaSphere ◽

10.1097/01.hs9.0000559732.57279.92 ◽

2019 ◽

Vol 3 (S1) ◽

pp. 142

Author(s):

A. Athanasiadou ◽

M. Gkaitatzi ◽

G. Papaioannou ◽

M. Iskas ◽

O. Asteriou ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Single Cell ◽

Prognostic Value ◽

Lymphocytic Leukemia ◽

Banding Analysis

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Echocardiographic Assessment of Aortic Pulse Wave Velocity as a New Diagnostic Parameter for Left Ventricular Diastolic Dysfunction

QJM ◽

10.1093/qjmed/hcaa041.008 ◽

2020 ◽

Vol 113 (Supplement_1) ◽

Author(s):

M A S Ammar ◽

A M Elshazly ◽

M F Ismail ◽

H G M Helmy

Keyword(s):

Prognostic Value ◽

Significant Positive Correlation ◽

Pulse Wave ◽

Aortic Pulse Wave Velocity ◽

Left Ventricular ◽

Control Group ◽

Case Group ◽

Diagnostic Parameter ◽

Positive Correlation ◽

Echocardiographic Assessment

Abstract Background The association between increased arterial stiffness and Left ventricular (LV) diastolic dysfunction (DD) has been well characterized, suggesting a close interaction between the arterial system and the left ventricle. Aortic pulse-wave velocity (PWV) is a measure of aortic stiffness, and it has an established prognostic role in cardiovascular diseases and in the general population. Aim Evaluation of aortic PWV assessed by echocardiography as a new diagnostic parameter for LV DD by correlation with current echocardiographic LV DD indices, and also evaluation of aortic PWV prognostic value in patients with DD by correlation with Brain natriuretic peptide (BNP). Methods This study was conducted at Ain-Shams and Helwan University hospitals from December 2017 to December 2018. It included 100 subjects aged from 55 to 60 years; they were divided into two groups, 1st group (case group): 80 patients with asymptomatic LV DD with preserved ejection fraction ≥50%, 2nd group (control group): 20 patients with normal diastolic function. All patients were subjected to full history and thorough physical examination. BNP, ECG and full echocardiography with assessment of aortic PWV were done. Results A total of 100 patients were enrolled, 38 (47.5%) males in case group vs. 9 (45%) in control group. Hypertension, diabetes and dyslipidemia were significantly higher in case vs. control (P-values: <0.001, 0.005, 0.002 respectively). Aortic PWV has significant positive correlation with both age and body mass index (r = 0.422, r = 0.847 respectively with P < 0.001 for both). Aortic PWV has significant positive correlation with E/e’ (r = 0.957, P < 0.001), tricuspid regurge velocity (r = 0.941, P < 0.001), and left atrial volume index (r = 0.947, P < 0.001), but it has significant negative correlation with septal e’ (r=-0.970, P < 0.001) and lateral e’ (r=-0.932, P < 0.001). Aortic PWV has significant positive correlation with plasma BNP level (r = 0.958, P < 0.001). Aortic PWV was significantly higher in case vs. control group with mean values (15.5±1.32 vs. 10.11±0.78 m/s respectively; P < 0.001). The area under the ROC curve for aortic PWV to detect DD was 0.86 (95% CI, 0.76–0.98; P < 0.001) and the optimal cutoff point of 12.5 m/s produced 92.3% sensitivity and 75.0% specificity (the positive and negative predictive values were 93.5 and 72.7%, respectively with an accuracy of 89.0%). Conclusion Echocardiographic assessment of aortic PWV appears not only to be a highly sensitive, reliable, easy, rapid and practical parameter for LV DD detection but also has a promising prognostic value in patients with LV DD.

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Mutational Status of the TP53 Gene As a Predictor of Response and Survival in Patients With Chronic Lymphocytic Leukemia: Results From the LRF CLL4 Trial

Journal of Clinical Oncology ◽

10.1200/jco.2010.32.0838 ◽

2011 ◽

Vol 29 (16) ◽

pp. 2223-2229 ◽

Cited By ~ 170

Author(s):

David Gonzalez ◽

Pilar Martinez ◽

Rachel Wade ◽

Sarah Hockley ◽

David Oscier ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Survival Data ◽

Prognostic Value ◽

Gene Mutations ◽

Progression Free Survival ◽

Tp53 Gene ◽

Lymphocytic Leukemia ◽

Tp53 Mutations ◽

Mutational Status ◽

Gene Tp53

Purpose TP53 mutations have been described in chronic lymphocytic leukemia (CLL) and have been associated with poor prognosis in retrospective studies. We aimed to address the frequency and prognostic value of TP53 abnormalities in patients with CLL in the context of a prospective randomized trial. Patients and Methods We analyzed 529 CLL samples from the LRF CLL4 (Leukaemia Research Foundation Chronic Lymphocytic Leukemia 4) trial (chlorambucil v fludarabine with or without cyclophosphamide) at the time of random assignment for mutations in the TP53 gene. TP53 mutation status was correlated with response and survival data. Results Mutations of TP53 were found in 40 patients (7.6%), including 25 (76%) of 33 with 17p deletion and 13 (3%) of 487 without that deletion. There was no significant correlation between TP53 mutations and age, stage, IGHV gene mutations, CD38 and ZAP-70 expression, or any other chromosomal abnormality other than 17p deletion, in which concordance was high (96%). TP53 mutations were significantly associated with poorer overall response rates (27% v 83%; P < .001) and shorter progression-free survival (PFS) and overall survival (OS; 5-year PFS: 5% v 17%; 5-year OS: 20% v 59%; P < .001 for both). Multivariate analysis that included baseline clinical variables, treatment, and known adverse genetic factors confirmed that TP53 mutations have added prognostic value. Conclusion TP53 mutations are associated with impaired response and shorter survival in patients with CLL. Analysis of TP53 mutations should be performed in patients with CLL who have progressive disease before starting first-line treatment, and those with mutations should be selected for novel experimental therapies.

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