Deregulation of the notch signaling pathway N B-cell chronic lymphocytic leukemia
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] B-cell Chronic Lymphocytic Leukemia (B-CLL) is the most common hematological malignancy in United States, characterized by CD5+ B-lymphocytes in peripheral blood. Deregulation of the Notch signaling pathway has been suggested to contribute to B-CLL pathogenesis [2-4]. Our objective was to characterize the differential expression of the Notch pathway genes in B-CLL cell lines as compared to normal B-cells and to determine if inhibiting the Notch pathway using γsecretase inhibitors (GSIs would lead to increased death in B-CLL cells. We observed over-expression of Notch pathway genes in three B-CLL cell lines. Treatment with either of the GSIs, DAPT(N-[N-(3, 5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl Ester) or Compound E, failed to have any effect on proliferation or death of these cells. Moreover,there was no alteration in transcription of downstream Notch target genes Hairy and enhancer of split 1, (HES1) Hairy/enhancer-of-split related with YRPW motif 1( HEY1), or Deltex homolog 1 (DTX1) in treated vs. untreated cells. These findings suggest that although Notch pathway genes seem to up regulated in B-B-CLL,inhibition of the pathway does not lead to cell death nor does it alter Notch target gene transcripton. One explanation could be that the Notch receptor is constitutively active in B-CLL as in other hematological malignancies like Tcell-Acute Lymphoblastic Leukemia (T-ALL). Alternatively, the survival of leukemic cells in B-CLL as well as transcription of the target genes examined, may be a combined result of signaling via the Notch and other signaling pathways such as Jak-STAT, Wnt and Sonic hedgehog, which have roles in B-CLL pathogenesis[6-10]. REFERENCES 1. Redaelli, A., et al., The clinical and epidemiological burden of chronic lymphocytic leukaemia. Eur J Cancer Care (Engl), 2004. 13(3): p. 279-87. 2. Rosati, E., et al., Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells. Blood, 2009. 113(4): p. 856-65. 3. Hajdu, M., L. Kopper, and A. Sebestyen, Notch-regulation upon Dll4-stimulation of TGFb-induced apoptosis and gene expression in human B-cell non-Hodgkin lymphomas. Scand J Immunol, 2010. 71(1): p. 29-37. 4. Hubmann, R., et al., Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia. Blood, 2002. 99(10): p. 3742-7. 5. Lee, S.Y., et al., Mutations of the Notch1 gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia, 2005. 19(10): p. 1841-3. 6. Hegde, G.V., et al., Hedgehog-induced survival of B-cell chronic lymphocytic leukemia cells in a stromal cell microenvironment: a potential new therapeutic target. Mol Cancer Res, 2008. 6(12): p. 1928-36. 7. Lu, D., et al., Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A, 2004. 101(9): p. 3118-23. 8. Martinez-Lostao, L., et al., Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia. Leuk Lymphoma, 2005. 46(3): p. 435-42. 9. Ingram, W.J., et al., Sonic Hedgehog regulates Hes1 through a novel mechanism that is independent of canonical Notch pathway signalling. Oncogene, 2008. 27(10): p. 1489-500. 10. Hsiao, H.W., et al., Deltex1 is a target of the transcription factor NFAT that promotes T cell anergy. Immunity, 2009. 31(1): p. 72-83.
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