Title:Novel Insights in Molecular Mechanisms of CLL
VOLUME: 18 ISSUE: 23
Author(s):Nicola Zanesi, Veronica Balatti, Arianna Bottoni, Carlo M. Croce and Yuri Pekarsky
Affiliation:Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, 460 W. 12th Ave, BRT room 1090, Columbus, Ohio 43210, USA.
Keywords:CLL, TCL1, miR-15/16, miR-29, DLEU7, NOTCH1, mature B-cells, ZAP-70 expression, mutations, transcription factors
Abstract:B-cell chronic lymphocytic leukemia (CLL), the most common leukemia, originates from an expansion of a rare population of
CD5+CD19+ mature B-cells. CLL occurs in two forms, aggressive and indolent. For the most part aggressive CLL shows high ZAP-70
expression and unmutated IgH VH, while indolent CLL is characterized by low ZAP-70 expression and mutated IgH VH. Despite detailed
studies of clinical features and chromosomal abnormalities in CLL, molecular details underlying disease development are still not entirely
clear. In the past several years, more and more such mechanisms have emerged. Recent studies clarified mechanistic details of how
activation of TCL1, a critical molecule in aggressive CLL, initiates this malignancy. In indolent CLL characterized by 13q14 deletions,
MiR-15/16 targeting BCL2 and MCL1 and DLEU7 targeting TNF pathway were proposed as tumor suppressors. Analysis of CLL coding
genome identified NOTCH1 as a frequent target of activating mutations. Interestingly most of these pathways have downstream activating
effects on the NF-kB family transcription factors. Several mouse models of CLL, confirmed importance of these pathways in the
pathogenesis of CLL. Here, we discuss what has been learned from these new pathways, and analyze how CLL mouse models confirm
newly discovered molecular mechanisms of CLL.
