CXCL12/CXCR4 axis in the pathogenesis of acute lymphoblastic leukemia (ALL): a possible therapeutic target

Abstract

Acute lymphoblastic leukemia (ALL) is the commonest childhood malignancy, accounting for approximately 80 % of leukemia in the pediatric group, and its etiology is unknown. This neoplasia is characterized by male predominance, high-risk features and poor outcome, mainly in recurrence patients and adults. In recent years, advances in the success of childhood ALL treatment were verified, and the rate of cure is over 80 % of individuals. However, there is a considerable scope for improving therapeutic outcome in this neoplasia. Improvements in ALL therapy might readily be achieved by developing additional biomarkers that can predict and refine prognosis in patients with ALL. In normal hematopoietic cells, cytokines provide the stimulus for proliferation, survival, self-renewal, differentiation and functional activation. Abnormalities of cytokines are characteristic in all forms of leukemia, including ALL. The stromal cell-derived factor-1 (SDF-1 or CXCL12) is a member of the CXC chemokine family that binds to CXC chemokine receptor 4 (CXCR4). The CXCL12/CXCR4 axis appears to play a role in dissemination of solid tumors and hematopoietic diseases. Understanding the mechanisms by which ALL cells are disseminated will provide additional information to expand therapeutic approach. Therefore, this review summarizes information relating to ALL cell biology, focusing specifically in a cytokine receptor important axis, CXCL12/CXCR4, that may have implications for novel treatment strategies to improve life expectancy of patients with this neoplasia.

Stromal cell-derived factor-1-directed bone marrow mesenchymal stem cell migration in response to inflammatory and/or hypoxic stimuli

“…35,36 Indeed, targeting the SDF-1/CXCR4 axis has offered a promising novel therapeutic approach for improving cell therapy by attracting circulating stem cells that are either exogenously infused or endogenously induced to migrate and home to diseased areas. [37][38][39][40] Given the finding that preconditioning cells prior to their in vivo delivery might enhance their targeted migration, we systemically investigated the effects of inflammatory and/or hypoxic stimuli on the migration of BMMSCs in culture and after implantation using in vitro and in vivo models. In particular, we aimed to identify whether a combination of inflammatory and hypoxic stimuli might be more efficacious than a single, focused pretreatment.…”

CARMA1 is a novel regulator of T-ALL disease and leukemic cell migration to the CNS

“…Few molecules are known to be associated with T-ALL CNS disease including CCR7, a chemokine receptor normally expressed on naïve T cells4. CXCR4 has also recently been shown to play a role in T-ALL initiation and progression5–7. The involvement of chemokine receptors as well as other molecules regulating cell motility suggests that regulation of T-ALL cell migration is likely to play an important role in T-ALL.…”

Possible involvement of tyrosine kinase inhibitors on the expression of CXCR4 in chronic myeloid leukemia

“…These data corroborate with several studies reporting important involvement of the CXCR4/CXCL12 axis as a potential target for new therapeutic strategies in leukemia patients. 25,26 CML was the first cancer in which an effective targeted-therapy has been outlined 27 , and once TKIs were developed, they were proved to be more efficient in controlling the disease than other types of chemotherapy, such as IFN-α or hydroxyurea. This therapy targets the tyrosine kinase BCR/ABL, which is responsible of leukemogenic events in CML, and the use of these inhibitors can reverse the malignant changes in the leukemic cells and/or cause cell apoptosis.…”