ABSTRACT
In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified microRNA-34a (miR-34a) as a major downstream target of p53. We monitored the expression of miR-34a during disease development in a murine B-CLL model. miR-34a was up-regulated more than 20-fold during the leukemic but not during the preleukemic phase. In the human system, B-CLL cells also had 4.6-fold higher miR-34a expression compared with B cells of healthy controls. In B-CLL cells of patients with p53 aberrations, miR-34a expression was consistently low. The broad distribution of miR-34a levels in p53 wild-type patients prompted us to study the correlation between single nucleotide polymorphism 309 (SNP309) in the intronic promoter of MDM2 and miR-34a expression. B-CLL cells of patients with the SNP309 GG genotype had significantly lower miR-34a expression levels compared with patients with the TT genotype (P = .002). Low miR-34a levels were able to predict shorter time to treatment (P = .003) and were associated with an abbreviated lymphocyte doubling time. Further, overexpression of miR-34a in primary B-CLL cells induced apoptosis. These findings suggest miR-34a as a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in B-CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/genetics , MicroRNAs/genetics , Polymorphism, Single Nucleotide , Proto-Oncogene Proteins c-mdm2/genetics , RNA, Neoplasm/genetics , Aged , Aged, 80 and over , Animals , Apoptosis , Case-Control Studies , Disease-Free Survival , Female , Gene Expression Regulation, Leukemic , Genes, p53 , Genotype , Humans , Introns , Leukemia, Experimental/etiology , Leukemia, Experimental/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Middle Aged , Promoter Regions, Genetic , Tumor Cells, CulturedABSTRACT
Chronic lymphocytic leukemia (CLL) is a malignancy mainly affecting elderly people and is still considered an incurable disease. Despite recent advances in CLL treatment, relapse rates are high and often accompanied by the development of resistance towards conventional chemotherapy. Thus, new agents are needed for the treatment of these patients. In recent years, our understanding of the biological mechanisms driving CLL pathogenesis has considerably improved, and novel treatment strategies are arising. This review summarizes recent insights in CLL biology and describes several new agents and treatment strategies that are currently explored in pre-clinical studies and early-phase clinical trials.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Antineoplastic Agents/therapeutic use , Apoptosis/genetics , Apoptosis/physiology , Humans , Receptors, Antigen, B-Cell/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/physiologyABSTRACT
Homing to secondary lymphoid organs and bone marrow (BM) is a central aspect of leukemic pathophysiology. We investigated the roles of the two major lymphocyte integrins LFA-1 and VLA-4 on B-cell chronic lymphocytic leukemia (CLL) cells in these processes. We found that the majority of CLL cells expressed significantly reduced LFA-1 due to low beta2 integrin transcripts. VLA-4 expression was heterogeneous but underwent rapid activation by the BM chemokine CXCL12. CLL cells failed to transmigrate across VCAM-1-expressing, ICAM-1-expressing, and CXCL12-expressing endothelium, whereas when LFA-1 expression was regained in subsets of CLL cells, these lymphocytes rapidly transmigrated the endothelium. Furthermore, when injected into tail veins of immunodeficient mice, normal B cells rapidly homed to lymph nodes (LN) in a LFA-1-dependent manner, whereas CLL cells did not. Nevertheless, only residual CLL subsets could reenter BM, whereas both normal and CLL cells homed to the mice spleen in an LFA-1-independent and VLA-4-independent manner. Our results suggest that CLL cells have a reduced capacity to adhere and transmigrate through multiple vascular endothelial beds and poorly home to lymphoid organs other than spleen. Integrin blocking could thus be an efficient strategy to prevent circulating CLL cells from reaching prosurvival niches in LNs and BM but not in spleen.
