Two papers and a KiKa grant on acute myeloid leukemia pathogenesis

3 May 2018

Transcription factors are frequently mutated in acute leukemia but how they contribute to disease pathogenesis at the molecular level remains largely unknown.

Anna Marneth and the group of Bert van der Reijden, theme Cancer development and immune defense studied two types of acute myeloid leukemia, each characterized by a different transcription factor mutation.

For one leukemia type it was shown that the promoter of the oncogene GFI1 was bound by the mutated transcription factor RUNX1-ETO resulting in extremely high GFI1 expression in this subgroup. Using leukemia mouse models, it was subsequently shown that high GFI1 expression was essential for leukemia initiation and maintenance, identifying GFI1 as therapeutic target in this leukemia type.

For the other type of leukemia, epigenetic studies showed that it is characterized by cryptic intragenic transcription activation and that the sites of intragenic transcription activation are bound by the mutated transcription factor KMT2A-MLLT3.

Collaborations with the group of Joost Martens, theme Cancer development and immune defense and the Khandanpour leukemia group, University of Essen, Germany, were fundamental to this work.

A recently awarded KiKa grant (650 K€) to group leaders Bert van der Reijden and Joost Martens will be used to further investigate the role of cryptic intragenic transcription activation in acute myeloid leukemia pathogenesis.

Publications:

1. GFI1 is required for RUNX1/ETO positive acute myeloid leukemia. Haematologica 
2. C-terminal BRE overexpression in 11q23-rearranged and t(8;16) acute myeloid leukemia is caused by intragenic transcription initiation. Leukemia

Bert van der Reijden