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Abstract
CLL is a clonal B cell neoplasm, it is well correlated with advancing age, but the precise cause is unknown. CLL is characterized by an extremely heterogeneous clinical course and prognosis, While some patients may have a normal life expectancy without requiring treatment, others die of drug resistant disease as early as within two years of presentation; yet there is no reliable prognostic index that can be used to group patients with CLL according to likely outcome or to guide treatment.
A number of clinical and biological factors of prognostic relevance, which may add to the classical assessment provided by the staging systems, have been identified in an attempt to design a risk adapted strategies ,These include clinical characteristics, such as age, gender and performance status, and laboratory parameters reflecting the tumor burden or disease activity, such as lymphocyte count, lactate dehydrogenase (LDH) increase, bone marrow infiltration pattern or lymphocyte doubling time. Recently more informative prognostic parameters have been identified: serum markers such as soluble CD23, ß2-microglobulin or thymidine kinase and genetic markers of tumor cells, such as genomic aberrations, gene abnormalities (p53, ATM), the mutation status of the variable segments of the immunoglobulin heavy chain genes (IgVH) or surrogate markers for these factors, such as CD38 and ZAP-70.
The understanding of the pathological mechanisms involved in CLL is helping to unfold the heterogeneity of this neoplasm and this continues to evolve. Using gene expression profiling, genomic aberrations, epigenetic modifications, gene mutations and deregulated microRNAs has been identified.
CLL is an archetypal example of a malignant condition caused by a failure in cell death mechanisms rather than escape from proliferative control. Therefore, recent research has focused on the issue of the dysreguated apoptotic machinery of the cll cells and the microenvironmental factors regulating death in CLL cells. Investigating molecular variables that can potentiate the longevity of CLL cells and can influence the patient outcome put a challenge to incorporate this information into the risk stratification of individual patients.
Autophagy is an evolutionary conserved and strictly regulated lysosomal pathway that degardes cytoplasmic material and organelles through the formation of autophagosomes; the morphological hallmark of the process. The formation of autophagosomes is controlled by a specific set of autophagy genes called atg genes. Autophagy is a survival pathway required for cellular viability during starvation; however if it proceeds to completion, autophagy can lead to cell death.
Autophagy functions as a stress response that is upregulated by starvation, oxidative stress, or other harmful conditions. Remarkably, autophagy has been shown to possess important housekeeping and quality control functions that contribute to health and longevity. Autophagy plays a role in innate and adaptive immunity, programmed cell death, as well as prevention of cancer, neurodegeneration and aging. In addition, impaired autophagic degradation contributes to the pathogenesis of several human diseases including lysosomal storage disorders and muscle diseases.