PS06. MOLECULAR AND CELLULAR PATHOGENESIS OF CHRONIC LYMPHOCYTIC LEUKEMIA
DIMITAR EFREMOV
ICGEB Hematology Group - Monterotondo Outstation, CNR Campus "A. Buzzati-Traverso", Rome, Italy
e-mail: efremov@icgeb.org
*Corresponding Author:
page: 17
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Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is the most common adult leukemia in the western hemisphere. It manifests with a variable clinical course that is characterized by progressive disease and short survival in approximately half of the cases and a relatively stable disease and normal life span in the remaining patients. In recent years, several features of the B-cell receptor (BCR) have been identified as major prognostic determinants in CLL, indicating an important role for antigen-stimulation in the pathogenesis of this disorder. In particular, the leukemic B-cells in patients with progressive disease typically express BCRs encoded by unmutated immunoglobulin variable heavy chain (VH) genes, whereas the VH genes are mutated in most patients with stable disease. Patients with progressive disease also usually express the protein tyrosine kinase ZAP-70, which is highly homologous to Syk, a key mediator of proximal BCR signaling. Additional support for a role of the BCR in the pathogenesis of aggressive CLL comes from the observation that the leukemic immunoglobulins in these patients are often encoded by identical VH/VL gene combinations, indicating that they have been stimulated and selected by a very limited set of antigens. Finally, engagement of the BCR by antigen induces activation of the PI3K/Akt and Raf/MEK/ERK pathways, which have been shown to play a prominent role in promoting the growth and survival of the leukemic B-cells. As such, the BCR and its downstream signalling pathways appear as attractive candidates for targeted therapy of CLL.
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