C-X-C Chemokine Receptor 4 in Chronic Lymphocytic Leukemia

Overview

Chronic lymphocytic leukemia is the most common type of chronic leukemia, accounting for approximately 40% of all leukemias and mainly affecting older individuals. As it has a highly variable clinical course, identification of molecular and biological prognostic markers has provided new insights into the risk stratification of patients with chronic lymphocytic leukemia.

Prognosis depends primarily on the stage of the disease at diagnosis. There is a correlation between disease stage and median survival. However, about 50% of patients in early stage will develop more advanced disease. Also there is marked variation in disease progression amongst patients with similar Stages . Extreme clinical heterogeneity is one of the hallmark features of chronic lymphocytic leukemia despite the identification of genetic and phenotypic markers that correlate with prognosis, the biological basis of this clinical variability remains unclear .. In addition, the interactions of chronic lymphocytic leukemia cells with the microenvironment in secondary lymphoid tissues and the bone marrow are known to promote chronic lymphocytic leukemia cell survival and proliferation. The median age at diagnosis is 72 years, in the last decades chronic lymphocytic leukemia is more often diagnosed also in younger individuals, with almost 15% Of patients Of 55 years old or younger. There is a gender predisposition, As men are more frequently affected by chronic lymphocytic leukemia than women (male: female ratio of 1.5-2:1). C-X-C chemokine receptor type 4 (CXCR4) is a chemokine and chemokine receptor pair playing critical roles in tumorigenesis. Overexpression of C-X-C chemokine receptor type 4 is a hallmark of many hematological malignancies including acute myeloid leukemia, chronic lymphocytic leukemia and non-Hodgkin's lymphoma, and generally correlates with a poor prognosis. A highly potent competitive antagonist of C-X-C chemokine receptor type 4 recently has been identified with suppression of cancer cells aggressiveness in a variety of cancers. The protein-coupled receptor C-X-C chemokine receptor type 4 is activated by stromal cell-derived factor 1 and is involved in the control of migration and homing of cells notably for engraftment of normal and neoplastic hematopoietic cells in the bone marrow (BM). Bruton's tyrosine kinase (BTK) is a key player in B-cell antigen receptor (BCR) signaling that regulates B-cell growth. In addition to B-cell antigen receptor signaling, Bruton's tyrosine kinase participates in signal transduction through growth-factor receptors, Toll-like receptors, integrins and G-protein-coupled receptors such as C-X-C chemokine receptor type 4 and C-X-C chemokine receptor type 5. Bruton's tyrosine kinase inhibition results in impaired C-X-C chemokine receptor type 4 chemokine receptor surface expression, signaling and function in chronic lymphocytic leukemia. inhibition of Bruton's tyrosine kinase function would lead to a loss of tumor volume by preventing replenishment after spontaneous or drug-induced death, and by subverting leukemia cell retention in and homing back to sustaining tissue niches. Decrease C-X-C chemokine receptor type 4 delays disease progression and prolongs survival

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