Exploiting biological diversity and genomic aberrations in chronic lymphocytic leukemia

Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
Leukemia & lymphoma (Impact Factor: 2.89). 12/2011; 53(6):1023-31. DOI: 10.3109/10428194.2011.631638
Source: PubMed


There is remarkable heterogeneity in the clinical course and biological characteristics of patient subgroups with chronic lymphocytic leukemia (CLL). Mutations of key tumor suppressors (ATM, miR-15a/16-1 and TP53) have been identified in CLL, and these aberrations are important "drivers" of the disease and some of its clinical characteristics. While some mutations are associated with poor outcome [particularly del(17p) and TP53 mutation], others are linked to a favorable clinical course [e.g. del(13q) as sole aberration]. In addition to genetic aberrations, antigen drive and microenvironmental interactions contribute to the pathogenesis of CLL. How the genetic aberrations impact on the process of antigen drive or microenvironmental interactions is currently unclear. Our improved understanding of the biology and clinical course of specific genetic subgroups is beginning to be translated into more specific and targeted treatment approaches. As a result, genetic subgroups are treated in distinct protocols. This review summarizes the contribution of the microenvironment and the most important genetic aberrations in CLL and how our improved knowledge of the biology of CLL may translate into improved treatment results.

1 Follower
12 Reads
  • Source
    • "s carrying a del ( 11q ) clone display inactivating mutations of the second ATM allele and these cases show a poor chemotherapy response , reminiscent of what has been described for TP53 - defective CLLs ( Austen et al . , 2007 ) . In addition , patients carrying a del ( 11q ) clone typically show rapid progression , and reduced overall survival ( Seiffert et al . , 2012 ) . As for TP53 , disabling ATM mutations are enriched in chemotherapy - treated patients , again suggesting that an inactivation of the pro - apoptotic DDR is selected for in CLL ( Puente et al . , 2011 ; Quesada et al . , 2011 ) . It remains to be seen whether the novel agents , including ibrutinib , idelalisib , ABT - 199 , obinotuzu"
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world and accounts for approximately 30% of adult leukemias and 25% of non-Hodgkin lymphomas. The median age at diagnosis is 72 years. During recent years numerous genetic aberrations have been identified that are associated with an aggressive course of the disease and resistance against genotoxic chemotherapies. The DNA damage-responsive proapoptotic ATM-CHK2-p53 signaling pathway is frequently mutationally inactivated in CLL either through large deletions on chromosome 11q (ATM) or 17p (TP53), or through protein-damaging mutations. Here, we focus on the role of ATM signaling for the immediate DNA damage response, DNA repair and leukemogenesis. We further discuss novel therapeutic concepts for the targeted treatment of ATM-defective CLLs. We specifically highlight the potential use of PARP1 and DNA-PKcs inhibitors for the treatment of ATM-mutant CLL clones. Lastly, we briefly discuss the current state of genetically engineered mouse models of the disease and emphasize the use of these preclinical tools as a common platform for the development and validation of novel therapeutic agents.
    Full-text · Article · Jun 2015 · Frontiers in Genetics
  • Source
    • "Expression of antigens was analyzed for fluorescence using a Particle Analyzing System (PAS) flow cytometer (Partec, Germany). The positive expression of CD38 in the test cell population was the presence of the antigen on at least 10 % of the cells [18]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. It is characterized by heterogeneous clinical course of the disease and new prognostic factors are still needed. CD74 plays an important role in signal transduction in B cell proliferation and survival pathway. CD74 expression has been shown in solid tumors and has been connected with poor prognosis and tumor progression. The aim of the study was to evaluate the expression of CD74 in chronic lymphocytic leukemia patients with combination with other known prognostic factors. Expression of CD74 was determined in 90 patients and 28 healthy controls. CD74 expression was significantly higher in CLL group than in controls. There was positive correlation between CD74 and ZAP70 expression (p = 0.008). High expression of CD74 was positively correlated with more advanced stage of the disease (p = 0.02). No correlation was shown between CD74 and sex, mutational status IgVH and time to first treatment.
    Full-text · Article · Jun 2013 · Medical Oncology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bladder cancer cells illustrate major disruptions in their DNA methylation patterns as compared with normal ones. Authors aimed to identify epigenetic molecular markers in urine for early detection of bladder cancer. We retrospectively analyzed the methylation status of RARβ(2) and APC genes in urine samples from 210 bladder cancer patients, 61 patients with benign urological diseases, and 49 healthy volunteers by using methylation-specific PCR. Methylated RARβ(2) and APC were significantly higher in bladder cancer patients (62.8%, 59.5%) than benign (16.4%, 5%) but not detected in healthy volunteers (0%) at (P < 0.0001). Both methylated genes showed no significant difference among clinicopathologic factors; however, they were detected in all grades and stages. Among the 128 patients with bilharzial bladder cancer, 94 (73.4%) showed methylated RARβ(2) and 86 (67.2%) showed methylated APC. Homoplasmic methylation pattern of both genes were only detected in bilharzial bladder cancer cases. Both sensitivities and specificities of the methylated genes for bladder cancer detection were superior to urine cytology and when altogether combined, the sensitivities improved to (91.8%), (93.5%), (91.9%), and (80.9%) in detection of: bladder cancer, non-muscle invasive bladder cancer, low-grade tumors, and bilharzial associated bladder cancer, respectively. Thus, methylated RARβ(2) and APC genes might be valuable urinary molecular markers for early detection of bilharzial and nonbilharzial bladder cancer.
    Full-text · Article · Jun 2011 · Cancer Epidemiology Biomarkers & Prevention
Show more