Study of Differential Expression of the Chemokine Receptors CXCR3, CXCR4 and CXCR5 by Hematological Malignant Cells: An Approach to Novel Therapy by Chemokine Receptor Neutralization and a Possible Role in Tumour Metastasis and Extramedullary Organ Infiltration

Background and Objectives: There is accumulating evidence that apart from their physiologic functions, chemokine receptors may also be involved in migration and dissemination of malignant hematopoietic cells. BM microenvironment plays an important role in regulation of growth, survival and differentiation of normal and leukemic hematopoietic progenitors. Direct contact with stromal cells is particularly important for survival of normal and leukemic progenitors. This process is likely to be directed by chemokines secreted by BM stroma and by their corresponding receptors on leukemic cells. Chemokine receptors expressed in variable amounts on leukemic cells are functionally active and may be involved in trafficking and in vivo motility of malignant hematopoietic cells and identified chemokine receptor neutralization may act as a potential treatment for hematological malignancies. Design and Methods: This study investigated the expression of three chemokine receptors CXCR3, CXCR4 and CXCR5 on malignant cells from 90 patients, 30 ALL, 30 AML and 30 NHL patients using flow cytometry. Results: CXCR3, CXCR4 and CXCR5, were expressed in 97%, 93% and 83% of ALL patients (p 0.05) and in 50%, 53% and 63% of NHL patients (p 0.05) respectively, while in AML patients, the three chemokine receptors were significantly higher (p 0.05) in M3, M4 and M5, interestingly, the three AML subtypes with organomegaly. Similarly, the three chemokine receptors expression was significantly higher (p 0.05) with organomegaly and massive lymphadenopathy in ALL and NHL patients respectively. Conclusions: BM microenvironment plays a crucial role in regulating survival, proliferation and differentiation of both normal hematopoietic and leukemic cells. Localization of hemopoietic progenitors and leukemic cells involves interaction of leucocyte adhesion molecules with counterligands present on BM stromal cells and extracellular matrix. Migration of leukemic cells might be dependent on the expression of chemokine receptors which is expressed by a number of malignant neoplasms and may have a role in tumour metastasis. Different patterns of chemokine receptors identify different malignant cells and may play a role in malignant cell circulation. Since a potential mechanism in trafficking of hematological malignant cells is the interaction of chemokine receptors, which is expressed on malignant cells and since hematological malignancies have the potential to infiltrate the liver, spleen, lymph nodes and brain, such extramedullary presentation is important to understand the biology of hematological malignancies and also for developing new prognostic parameters and potential therapeutic approaches.