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BBB Seminar: Emmet McCormack

Co-inhibition of MDM2 and HDAC synergistically activate p53 mediated apoptosis in acute myeloid leukemia

Emmet McCormack,
Section for Haematology, Institute of Medicine, University of Bergen

Although mutations of the TP53 tumor suppressor gene are rare in acute myeloid leukemia (AML), wild-type p53 function is habitually annulled through over-expression of the MDM2 (murine double minute 2) oncoprotein or through various mechanisms including epigenetic silencing via histone deacetylases (HDACs). We hypothesized that binary antagonism of MDM2 and HDACs, with nutlin-3 and valproic acid would additively inhibit growth in leukemic cells expressing wild-type TP53 and induce p53-mediated apoptosis. In vitro studies with the combination demonstrated synergistic induction of apoptosis in AML cell lines and patient cells. Mechanisms included massive induction of p53, acetylated p53 and p53 target genes in comparison to either agent alone. The inhibitory effect of the combinational therapy upon proliferation was correlated to the clinical parameters of the patients, where CD34 negative patient samples demonstrated significantly better response in comparison to CD34 positive samples. To evaluate the combination in vivo, we developed an orthotopic, NOD/SCID IL2rγnull xenograft model of MOLM-13 cells (AML FAB M5a; wt TP53) expressing firefly luciferase. Survival analysis and bioluminescent imaging demonstrated the superior in vivo efficacy of the dual inhibition of MDM2 and HDAC in comparison to controls. Our results suggest the concomitant targeting of MDM2-p53 and HDAC inhibition, may be an effective therapeutic strategy for the treatment of AML.

Host: Helge Wiig, Department of Biomedicine