Molecular Mechanisms in Differentiation - Induction in Acute Promyelocytic Leukemia.

Abstract

Contains fulltext : 70517.pdf (publisher's version ) (Open Access)Leukemia is a hematological malignancy that is characterized by the clonal expansion of immature hematopoietic cells, which have escaped from the tightly coordinated cell cycle regulation, differentiation and apoptosis controls. In general, leukemia is characterized by a variety of mutations in pathways that are required for normal hematopoiesis. This thesis describes target genes of the mutated transcription factor PML-RAR , which is expressed in acute promyelocytic leukemia (APL) cells. APL, which accounts for 5-10% of all acute myeloid leukemias (AMLs), represents the best prognostic group amongst the different forms of leukemia having the highest curability. APL requires a unique form of treatment, which constitutes the first successful form of leukemia therapy that is based on induction of differentiation of the malignant cells, using all-trans retinoic acid (ATRA). The addition of pharmacological doses of ATRA to standard chemotherapy has led to an improvement of cure rates from 40% with chemotherapy alone to up to 90% when combined with ATRA. The identification of the chromosomal translocation t(15;17), which causes the expression of the chimeric oncoprotein PML-RAR and which is the genetic hallmark of APL, is important to establish the diagnosis. ATRA has been proven to directly target the product of this molecular defect and the APL model provides an example of targeted therapy based on differentiation induction. In this thesis we describe the identification of three ATRA-responsive genes in APL cells that are transcriptionally regulated by PML-RAR via a novel mechanism. Their biological function and their mechanism of action were studied in more detail in APL cellsRU Radboud Universiteit Nijmegen, 17 januari 2008Promotor : Witte, T.J.M. de Co-promotores : Jansen, J.H., Reijden, B.A. van der159 p