EVI1 in Acute Myeloid Leukemia

To diagnose patients with acute myeloid leukemia (AML) in an optimal manner, the combined application of conventional and modern cytogenetics with state-of-the-art molecular diagnostics is a requirement. Although at present, the WHO accurately classifies an array of human AML patients based on karyotyping combined with molecular diagnostic procedures, insight into the molecular defects of human AML is still increasing. As a result of that, the classifi cation of AML will be approved in the upcoming years. The focus of this thesis was to increase our understanding of specific subtypes of human leukemia. We focused on AMLs with chromosome 3q rearrangements, in particular on patients with an inv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 (shortly: (inv(3)/t(3;3)), frequently associated with ab

BCR-ABL1 tyrosine kinase sustained MECOM expression in chronic myeloid leukaemia

MECOM oncogene expression correlates with chronic myeloid leukaemia (CML) progression. Here we show that the knockdown of MECOM (E) and MECOM (ME) isoforms reduces cell division at low cell density, inhibits colony-forming cells by 34% and moderately reduces BCR-ABL1 mRNA and protein expression but not tyrosine kinase catalytic activity in K562 cells. We also show that both E and ME are expressed in CD34<sup>+</sup> selected cells of both CML chronic phase (CML-CP), and non-CML (normal) origin. Furthermore, MECOM mRNA and protein expression were repressed by imatinib mesylate treatment of CML-CP CD34<sup>+</sup> cells, K562 and KY01 cell lines whereas imatinib had no effect in non-CML BCR-ABL1 −ve CD34<sup>+</sup> cells. Together these results suggest that BCR-ABL1 tyrosine kinase catalytic activity regulates MECOM gene expression in CML-CP progenitor cells and that the BCR-ABL1 oncoprotein partially mediates its biological activity through MECOM. MECOM gene expression in CML-CP progenitor cells would provide an in vivo selective advantage, contributing to CML pathogenesis

Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity

A new mouse in which an IRES-GFP cassette is knocked-in to the Evi1 locus reveals that HSC long-term multilineage repopulating activity specifically segregates with expression of the Evi1 transcription factor