Genetic and epigenetic search for tumor suppressor genes on chromosome 7q in acute myeloid leukemia

Acute myeloid leukemia (AML) is one of the most frequent hematopoietic malignancies in adults. Therapies are stratified based on subgroups defined by the presence of recurrent chromosomal aberrations and/or gene mutations. Consequently, prognosis and clinical outcome of the disease is linked to the patterns of molecular and cytogenetic abnormalities.

Loss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias that are highly associated with myelodysplastic syndrome and AML, in particular with therapy-related or secondary MDS/AML.

Preliminary data obtained in our research consortium allowed the identification of three defined commonly deleted segments (CDS) on 7q suggesting the location and involvement of several tumor suppressor genes in AML. Furthermore, epigenetic profiling of these regions identified potential candidate genes silenced by both genetic and epigenetic alterations.

Our hypothesis for this project is that the deletion contributes to silencing of a dominantly acting tumour suppressor, whereby a “second hit” of the remaining allele is obtained by epigenetic inactivation and disruption of the gene’s function. This hypothesis will be tested on several candidate genes already identified in an epigenetic screen using functional assays in cell culture systems and primary human AML cells with well defined genetic alterations.

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