Analyse von Mikrosatelliteninstabilität und hMSH2-Expression bei Patienten mit akuter myeloischer Leukämie
Analysis of microsatellite instability and hMSH2 expression in patients with acute myeloid leukemia
von Petra Kohaus
Datum der mündl. Prüfung:2017-06-20
Erschienen:2017-06-12
Betreuer:Prof. Dr. Frauke Alves
Gutachter:Prof. Dr. Frauke Alves
Gutachter:Prof. Dr. Peter Burfeind
Gutachter:Prof. Dr. Martin Oppermann
Dateien
Name:PetraKohaus.pdf
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Zusammenfassung
Englisch
Acute myeloid leukemia, the most common acute leukemia in adults, is a malignant, genetically heterogeneous, clonal disorder, which is based on haemopoietic progenitor cells with a disrupted ability of self-renewal, proliferation and differentiation in consequence of an accumulation of acquired genetic alterations. Chromosomal and moleculargenetic alterations are amongst the most important prognostic markers and could be used to develop new targeted therapies. To identify the influence of DNA mismatch repair associated proteins on the pathogenesis of AML, bone marrow samples from 40 AML patients were investigated about microsatellite instability (MSI) and expression of the DNA mismatch repair associated protein hMSH2. Interestingly, no MSI was detected in any of the 40 patients. Loss of heterozygosity (LOH) was found in 25% of the patients. The portion of patients with secondary AML showed LOH in 44%, whereas in patients with de-novo AML, LOH could be detected in only 19,4%. The most common LOH was for the marker NF1 with 50% of all LOH. The predominant part of the patients showed a low expression of hMSH2. There was no correlation of decreased hMSH2 expression with caryotype alterations or MSI. The lack of MSI in the patients investigated indicates that MSI is not the only factor contributing to the pathogenesis of AML. Equally, the decreased expression of the hMSH2 protein that we found immunhistochemically in bone marrow samples as well as in western blot, suggests a minor role in the pathogenesis of AML because of the missing correlation with caryotype alterations or LOH. The increased appearance of LOH in patients with secondary AML as compared to patients with de-novo AML indicates that this might be a later or therapy induced event. The notably frequent detection of LOH at the marker NF1 would be a worthwhile target of further investigations.
Keywords: acute myeloid leukemia; microsatellite instability; hMSH2; LOH; MSI; loss of heterozygosity; NF1; DNA mismatch repair system