Abstract
Differentiation of blood cells is one of the most complex processes in the body. It is regulated by the action of transcription factors in time and space which creates a specific signaling network. In the hematopoietic signaling system, Notch is one of the main regulators of lymphocyte development. The aim of this study was to get insight into the regulation of Notch signalization and the influence of poly(ADP-ribose)polymerase (PARP) activity on this process in three leukemia cell lines obtained from B and T cells. PARP1 is an enzyme involved in posttranslational protein modification and chromatin structure changes. B and T leukemia cells were treated with Notch and PARP inhibitors, alone or in combination, for a prolonged period. The cells did not show cell proliferation arrest or apoptosis. Analysis of gene and protein expression set involved in Notch and PARP pathways revealed increase in JAGGED1 expression after PARP1 inhibition in B cell lines and changes in Ikaros family members in both B and T cell lines after γ-secretase inhibition. These data indicate that Notch and PARP inhibition, although not inducing differentiation in leukemia cells, induce changes in signaling circuits and chromatin modelling factors.
Highlights
Today great efforts are being undertaken in the development of differentiation programs for cancer and leukemia cells to stop their proliferation and to change their biology
We investigated the possibility of cellular reprogramming by prolonged inactivation of NOTCH and PARP pathways in different leukemia cell lines of B and
We showed that long-term treatment could cause changes in expression of signaling molecules, possibly other pro-survival signaling circuits dominated over Notch pathway, enabling these cells to be resistant to apoptosis and differentiation
Summary
Today great efforts are being undertaken in the development of differentiation programs for cancer and leukemia cells to stop their proliferation and to change their biology. We investigated the possibility of cellular reprogramming by prolonged inactivation of NOTCH and PARP pathways in different leukemia cell lines of B and T origin. The pathway activation depends on a specific Notch receptor cleavage by γ-secretase, after ligand binding. Released Notch intracellular domain (NICD) can recruit activation complex to the promoter sequence RBPJ present in target genes. Its main role is to direct lymphocytes toward T cell line, it has a role in certain steps of B cell and other blood cell differentiation. Its constitutive activation was found to drive tumorigenesis in different types of leukemia, such as T cell acute lymphoblastic leukemia (T-ALL) and B cell chronic lymphocytic leukemia (B-CLL) [2,4,5]
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