Salek-Ardakani, S.; (2008) Investigating the molecular basic of AMKL and MDS. Doctoral thesis , University of London.

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Abstract

Malignant haematopoiesis is usually associated with various genetic lesions such as chromosomal translocations or mutations in individual genes. This thesis investigates the genetic basis of two such syndromes, acute megakaryoblastic leukaemia (AMKL) and myelodysplastic syndrome (MDS). The most common constitutional aneuploidy with predisposition to leukaemia is trisomy 21, also known as Down Syndrome (DS). DS children have a 500-fold increased risk for AMKL. Somatic mutations acquired during foetal haematopoiesis in the GATA1 transcription factor are detected in megakaryoblasts from all the DS patients with AMKL. Here we show that the Gatal mutation co-operates with the chromosome 21 gene, ERGS, to immortalize foetal megakaryocyte progenitors with the phenotype of AMKL megakaryoblasts. We show that ERG-3 promotes megakaryopoiesis and acts as an oncogene and that progenitor cells harbouring a Gatal mutation plus ERG-3 or ERG-3 alone lead to rapid development of leukaemia in vivo. Our data support a model where trisomy 21 overexpressed genes, that promote foetal megakaryopoiesis, co-operate with mutations that arrest development and lead to DS-AMKL. This is also the first direct demonstration of the leukaemogenic activity of full length ERG protein, possibly explaining the poor prognosis of the acute myeloid leukaemias with high expression of ERG. DS patients are also predisposed to TMD (transient myeloproliferative disorder) and MDS (myelodysplastic syndrome) prior to AMKL development. Myelodysplastic syndromes are a group of clonal haematopoietic disorders, characterised by aberrant proliferation and differentiation of cells of the myeloid lineage resulting in severe cytopenia and dysplasia of myeloid, erythroid and megakaryocytes. The most common chromosomal translocation associated with MDS is the t(3 5)(q25q35) translocation. This rearrangement results in a fusion transcript comprised of nucleophosmin (NPM) gene and myeloid leukaemia factor 1 (MLF1) gene. To determine the importance of the NPM-MLF1 fusion protein in the development and progression of MDS to AML, its role in myelopoiesis and megakaryopoiesis was investigated. Our results show that NPM-MLF1 affects the differentiation of myeloid cells. Our preliminary data predicts that NPM may have a role in megakaryopoiesis and its interaction with NPM-MLF1 may affect the function of the fusion protein.

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