engleski

Ikaros and Notch family mesh network and its role in B-lymphocytic leukemia

Notch signalling pathway belongs to a group of highly conserved mechanisms within the cell, which is present in most multicellular organisms. Mesh network of molecules, which are part of Notch signalling pathway, consists of receptors (Notch 1-4) and its Delta-like (1, 3, 4) and Jagged (1, 2) ligands. Notch activation is an important part of many cellular processes, including proliferation, differentiation, hematopoiesis, oncogenesis, embryogenesis and apoptosis. In lymphocyte development, Notch can become a major mediator of cell division or growth, as well as regulator of apoptosis process. Ikaros transcription factors belong to a family of proteins structurally recognizable by zinc finger motifs, which are arranged in two groups: the N-terminal (essential for binding to DNA) and C-terminal part of the sequence, through which the protein can form homo- or heterodimers. Its family consists of 5 members: Ikaros, Helios, Aiolos, Eos and Pegasus. Those factors, together with members of the Notch signalling pathway are the crucial elements of normal lymphopoiesis. Mutations responsible for the reduction of Ikaros activity and overactivation of Notch are mainly responsible for leukemogenesis promotion. It has been shown that Ikaros controls the expression of several target genes which are part of the Notch signalling pathway (pTα, Hes1, Deltex1, Gata3, and Runx1). In some cases, Notch1 also acts as an oncoprotein. Its role is best studied in T-ALL, an aggressive form of leukemia that usually affects children and adolescents. Recent studies showed that Notch plays a key role in development of B cell chronic lymphocytic leukemia. Loss of function analyses showed that Notch1 is responsible for liver and skin cancer development in mice. However, the connection between Ikaros family members and the Notch signalling pathway in B-CLL remains poorly understood. The aim of this research was to investigate the interactions of Ikaros and Notch family mesh network in B-CLL development. By means of single cell quantitative real time multiplex polymerase chain reaction we followed the coexpression of Notch and Ikaros family transcription factors and compared it with the clinical data. Also, we determined the apsolute copy number of Notch1 and Aiolos mRNA molecules per cell. Overall, Notch1 mRNA expression is decreased in malignant CD5+19+ leukemic cells when compared with healthy CD19+ peripheral blood B-lymphocytes. We further found that malignant samples have a higher frequency of Notch1 positive cells. The implications on this mesh network will be discussed.

Notch signalling ; Ikaros transcription factors

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