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Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia
Abstract<sec> <title>Background

Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy.

Methods

Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro.

Results

We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.

Conclusion

Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.

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Publication Date
Sun Jul 03 2005
Journal Name
Journal Of The Faculty Of Medicine Baghdad
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Publication Date
Sun Jul 03 2011
Journal Name
Journal Of The Faculty Of Medicine Baghdad
mRNA in situ hybridization analysis of VEGF in chronic lymphocytic leukemia

Background: Several factors render chronic lymphocytic leukemia (CLL) an interesting subject for study by researchers. These include marked progress in understanding the molecular biology of normal and neoplastic lymphocytes and recent advances in molecular genetics techniques. Among molecular markers, vascular endothelial growth factor (VEGF), have been widely studied.
Objective: The aim of the study is to evaluate the role of VEGF in the pathogenesis of CLL and its role in disease progression.
Patients, materials and methods: A retrospective cross-sectional study was done on 60 patients with chronic lymphocytic leukemia (45 males & 15 females) compared with 20 controls (anemic patients), all recr

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Publication Date
Mon Jul 01 2013
Journal Name
Journal Of The Faculty Of Medicine Baghdad
Immunohistochemical analysis of CD34 to evaluate angiogenesis in chronic lymphocytic leukemia

Background: Chronic lymphocytic leukemia (CLL) results from a progressive accumulation of long-lived, functionally incompetent, nonproliferating lymphocytes.
Angiogenesis is defined as the formation of new capillaries from pre-existing blood vessels and plays an important role in the progression of solid tumors as well as several hematologic malignancies like CLL.
Patients and methods: A retrospective cross-sectional study done on 68 patients with CLL compared with 15 control individuals (anemic patients), all recruited at the Medical City Teaching Laboratories from January 2005 to December 2008. The bone marrow biopsy (BMB) of each was re-examined histologically. Immunohistochemical (IHC) technique was performed on BMB sections ut

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Publication Date
Sun Jul 01 2012
Journal Name
Journal Of The Faculty Of Medicine Baghdad
mRNA in situ hybridization analysis of MMP-9 in chronic lymphocytic leukemia

Background: Several factors render chronic lymphocytic leukemia (CLL) an interesting subject for study by researchers. These include marked progress in understanding the molecular biology of normal and neoplastic lymphocytes and recent advances in molecular genetics techniques. Among molecular markers, matrix metalloproteinase-9 (MMP-9), have been widely studied.
Objectives: The aim of the study is to evaluate the role of MMP-9 in the pathogenesis of CLL and to assess its prognostic role.
Patients and methods: A retrospective cross-sectional study done on 60 patients with chronic lymphocytic leukemia compared with 20 controls (anemic patients), all recruited at the Medical City Teaching Hospital laboratories from January 2004 to De

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Publication Date
Sun Jul 04 2010
Journal Name
Journal Of The Faculty Of Medicine Baghdad
mRNA in situ hybridization analysis of p-53 cancer suppression gene and Bcl-2 oncogene in chronic lymphocytic leukemia

Background: Several factors render chronic lymphocytic leukemia (CLL) an interesting subject for study by researchers. These include marked progress in understanding the molecular biology of normal and neoplastic lymphocytes and recent advances in molecular genetics techniques. Among molecular markers, p53 cancer suppressor gene and the antiapoptotic gene Bcl-2 have been widely studied. 
Patients and methods: A retrospective cross-sectional study done on 60 patients with chronic lymphocytic leukemia compared with 20 controls (anemic patients), all recruited at the Medical City Teaching Hospital laboratories from January 2004 to December 2007. The bone marrow biopsy of each was re-examined histologica

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Publication Date
Wed Jan 02 2013
Journal Name
Journal Of The Faculty Of Medicine Baghdad
Evaluation of Bcl 2 and Ki 67 expression in Chronic Lymphocytic Leukemia .

Background :Chronic lymphocytic leukemia (CLL) is a low-grade B-lineage lymphoid malignancy. Both  Ki-67 which is a large nuclear protein associated with cell proliferation and Bcl-2 which is an anti-apoptotic protein which is associated with dysregulation of the intrinsic apoptotic pathway , were thoroughly investigated in many cancer patients particularly in hemopoietic malignancies .

Patients, materials and methods: This retrospective study was conducted from November 2009 to May 2010 , on fifty formaline fixed paraffin embedded blocks of CLL cases retrieved from Medical City Teaching Hospital ; their age range was 39-75 years along with twenty control cases with benign r

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Publication Date
Sun Jan 03 2016
Journal Name
Journal Of The Faculty Of Medicine Baghdad
Alcohol and drug abuse in post-conflict Iraq

Background: The 2006-2007 Iraqi Mental Health survey (IMHS) reported surprisingly low prevalence of alcohol and drug abuse in the Iraqi population. Since then anecdotal and clinical reports have suggested that abuse of alcohol and drugs in Iraq has increased. To investigate this possibility, we conducted a survey of drug and drug abuse at youth centers in Baghdad.
Objective: To investigate this possibility, we conducted a survey of drug and drug abuse at youth centers in Baghdad.
Patients and methods: A total of 2678 persons were included in this survey with male to female ratio of 3.8:1. They were randomly selected from youth centers located in different sectors in Baghdad (Sader city, Al-Rusafa side and Al-Karkh side). Composite

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Publication Date
Mon Apr 01 2013
Journal Name
Journal Of The Faculty Of Medicine Baghdad
Combination therapy of Fludarabine and Cyclophosphamide(FC) Combination Regimen in advance stage of Chronic Lymphocytic Leukemia

Background: the exposure of  chronic lymphocytic leukemia (CLL) cells to fludarabine and cyclophosphamide resulted in an increased, synergistic cytotoxicity . DNA repair mechanisms in CLL cells, which are initiated in response to cyclophosphamide exposition, are inhibited by fludarabine. This observation was later translated into clinical trials evaluating the combination of fludarabine plus cyclophosphamide (FC) showed promising efficacy with response rates exceeding 90% in previously untreated and pretreated patient

Aim of  this study: To assess the efficacy and safety of combination therapy of fludarabine plus cyclophosphamide in  Iraqi adults patients with advance stage of chro

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Publication Date
Wed Apr 01 2015
Journal Name
Journal Of The Faculty Of Medicine Baghdad
Immunohistochemical study of p-53 protein expression in chronic lymphocytic leukemia and its correlation with clinicopathological factors

Background: several factors render chronic lymphocytic leukemia an interesting subject for study by researchers. These include marked progress in understanding the molecular biology of normal and neoplastic lymphoid cells and recent advances in molecular genetics techniques. Among molecular markers, p-53 cancer suppressor gene has been widely studied.
Objectives: is to correlate p-53 protein expression in chronic lymphocytic leukemia, as examined by immunohistochemical method, with some pathological and clinical parameters.
Patients and methods: this is a retrospective study; whereby archival paraffin-embedded bone marrow tissue blocks along with the clinical and hematological records of fifty patients (35 males and 15 females), wi

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Publication Date
Sat Jun 01 2019
Journal Name
Journal Of Economics And Administrative Sciences
NONPARAMETRIC And Semiparametric Bayesian Estimators in survival function analysis

 Most statistical research generally relies on the study of the behaviour of different phenomena during specific time periods and the use of the results of these studies in the development of appropriate recommendations and decision-making and for the purpose of statistical inference on the parameters of the statistical distribution of life times in  The technical staff of most of the manufacturers in the research units of these companies deals with censored data, the main objective of the study of survival is the need to provide information that is the basis for decision making and must clarify the problem and then the goals and limitations of this study and that  It may have different possibilities to perform the

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