CCND2 is a RUNX1/ETO target required for leukaemic propagation

Introduction:

The chromosomal translocation t(8;21) is the most common rearrangement in AML and generates the fusion protein RUNX1/ETO. RUNX1/ETO is traditionally thought as a transcriptional repressor, however, we have identified many target genes upregulated upon its binding.

Results:

Performing an in vitro and an in vivo shRNA screen targeting those genes, we identified CCND2 as a required factor for RUNX1/ETO expressing cells propagation. CCND2 down regulation leads to a block in G1 phase, decreased proliferation and clonogenicity. Since heterodimerisation of CCND2 with the G1 CDKs CDK4 or 6 activates their kinase activities, we explored pharmacologic inhibition of G1 CDK-CCND complexes with palbociclib. Treatment with palbociclib inhibited G1 cell cycle progression and led to an increase median survival in xenotransplantation models. Importantly, combination of palbociclib with the ABL/KIT inhibitor imatinib resulted in a strongly synergistic inhibition of cell proliferation. We are currently exploring the in vivo efficacy of this and other combos.

Conclusion:

Taken together, t(8;21) positive AML cells are dependent on CCND2 offering new opportunities for drug combinations with reduced genotoxic toxicity.