The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

Mir-55 inhibition can reduce cell proliferation and induce apoptosis in Jurkat (Acute T cell Leukemia) cell line.

BACKGROUND: MicroRNAs are small and non-coding RNA molecules with approximately 22 nt in length that cause inhibition of translation or degradation of mRNA. MiR-155 is a kind of molecule with different functions, such as its role in proliferation, apoptosis, inflammation, differentiation, and immunity. One of its best known functions is apoptosis that affects on caspase-3 activity. The main aim of this study was evaluation of miR-155 inhibition effect on cell proliferation and apoptosis induction in Jurkat cells. MATERIAL AND METHODS: In this study, Jurkat cells along with MTT assay were used for evaluation of sensitivity to varied concentrations of miR-155 inhibitor (25, 50 and 75 nmol). MiR-155 expression level was analyzed using the quantitative real-time polymerase chain reaction (QRT-PCR). Caspase-3 activity was measured by caspase-3 colorimetric activity assay kit. Unpaired t-test was applied for the analysis of MTT and apoptosis results. Probability of 5% was assumed as statistically significant. RESULTS: According to our results, the use of miR-155 inhibitor increased the activity of caspase-3 by 2 fold in 75 nmol concentration. In this research, we found that the proper increase of miR-155 inhibitor concentration can inhibit miR-155 and consequently increase caspase-3 activity and induce apoptosis in the Jurkat cells leading to cell death ultimately. CONCLUSIONS: Apoptosis induction by miRNAs activation or inhibition is probably one of the best and low risk ways of cell death induction in malignancies. Due to role of miR-155 in several cancer cells, it may be used as a therapeutic target in future.

Increased susceptibility to apoptosis in CD45(+) myeloma cells accompanied by the increased expression of VDAC1.

Expression of CD45 is quite variable in human myeloma cells and cell lines, such as U266, and CD45(+) U266 proliferates in response to a growth factor, interleukin-6. Here, we show that CD45(+) myeloma cell lines were more sensitive to various apoptotic stimuli, such as oxidative stress and endoplasmic reticulum (ER)-stress, than CD45(-) cells. Reactive oxygen species and calcium ion seemed to be involved in the susceptibility to apoptosis of CD45(+) U266. The activation of the src family kinases associated with CD45 phosphatase played an important role in the augmented apoptosis in CD45(+) U266 by oxidative stress. These results indicate that the CD45-expression renders myeloma cells competent for not only mitogenic but also apoptotic stimuli, resulting in either proliferation or apoptosis of CD45(+) myeloma cells dependently upon the circumstantial stimuli. Furthermore, voltage-dependent anion channel (VDAC) 1 was identified as a gene highly expressed in CD45(+) U266 by cDNA subtraction. The increased expression of VDAC1 seemed to augment the sensitivity to the ER-stress because the VDAC1-transfected U266 was more susceptible to the thapsigargin-induced apoptosis. Thus, CD45 expression accompanied by the increased VDAC1 expression sensitizes myeloma cells to the various extracellular stimuli that trigger apoptosis via the mitochondrial pathways.

Proliferation of immature myeloma cells by interleukin-6 is associated with CD45 expression in human multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy of human plasma cells, and myeloma cells can be classified into several subpopulations according to phenotypic differences, such as CD38 MPC-1- CD49e- immature, CD38 MPC-1+ CD49e- intermediate and CD38 MPC-1+ CD49e+ mature myeloma cells. The expression of the CD45 molecule on myeloma cells is quite variable, and the physiological consequence of CD45 on myeloma cells is still unknown. Recently, we have found that a few MPC-1- immature myeloma cells express CD45 antigens while most myeloma cells do not express the CD45. MPC-1- CD45+ CD49e- but not MPC-1- CD45- CD49e- immature cells contain proliferating cells in response to interleukin-6 (IL-6). IL-6 can also induce expression of CD45 on the MPC-1- CD45- subpopulation of immature myeloma cells. In addition, myeloma cell lines responding to IL-6 express CD45, whereas cell lines proliferating independent of IL-6 do not express CD45. In the U266 cell line, IL-6 leads to the induction of CD45 expression and cell proliferation, indicating that IL-6-induced effects are closely linked to CD45 expression. Thus, there is a heterogeneity in human myeloma cells, and among these subpopulations immature myeloma cells expressing the CD45 molecules appear to proliferate in response to IL-6. In this review we propose the involvement of CD45 in MM pathogenesis, and the possible implications of CD45 as both a phenotypic marker and a functional molecule is discussed.