engleski

Transcription factors abnormalities associated with lymphoid malignancies

Ikaros gene family encodes for a group of Kruppel-like zinc-finger proteins which act as lymphoid-specific transcription factors. Apart from Ikaros, this group includes Aiolos, Helios, Eos and Pegasus. Knock-out studies on mice have shown that Ikaros, Aiolos and Helios function as transcription regulators playing an important role in differentiation of particular subsets of lymphocytes. All members of Ikaros gene family share the similarity in their overall structure. The four N-terminal zinc-finger motifs are responsible for sequence-specific DNA-binding, while C-terminal zinc-finger pair acts as a dimerization domain: homo- and heterodimers of Ikaros, Helios and Aiolos bind DNA with high affinity in a sequence-specific manner. These complexes can then activate or repress transcription from certain promoters if the DNA-binding domains of both members of the complex are intact. However, by the mechanism of alternative splicing different isoforms can be created that lack one or more N-terminal zinc-fingers. These non-DNA binding isoforms act as dominant-negative because complexes contain at least one such molecule cannot bind DNA efficiently. There is a possibility that up regulated production of shorter isoforms could result in phenotypes seen in knock-out mice which include complete or partial arrests in different stages of lymphocyte development, leading to development of leukemia and lymphomas. Therefore we decided to correlate the expression of long and short isoforms of these proteins in bone marrow, peripheral blood lymphocytes and lymph nodes of patients with different lymphoproliferative disorders. Using reverse-transcription-polymerase chain reaction (RT-PCR) we analyzed lymph nodes from patients with different types of leukemia. Eight human hematological cell lines were also screened for the expression of Aiolos and Helios. Preliminary results show a heterogenous pattern of expression of Aiolos and Helios among these samples. Shorter isoforms, which are probably generated in smaller amounts than fully functional molecules, will be detected by more sensitive real-time PCR and different subpopulations of cells will be analyzed using flow cytometry. The results could improve our understanding of the mechanisms of normal lymphocyte differentiation and possible pathways in development of human lymphoproliferative disorders.

Aiolos; Ikaros; Lymphoma; Transcription factors

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