t(8;21) Acute Myeloid Leukaemia Requires Active CCND-CDK4/6

Introduction: The leukaemic fusion oncoprotein RUNX1/ETO, which results from the t(8;21) translocation, establishes a novel transcriptional programme maintaining leukaemia.

Results: Functional interrogation of direct RUNX1/ETO target genes with an RNAi screen identified CCND2 as a crucial transmitter of RUNX1/ETO-driven maintenance of leukaemia both in tissue culture and in an NSG xenograft model. Knockdown of CCND2 caused a G1 cell cycle arrest and inhibited leukaemic proliferation and clonogenicity similarly to RUNX1/ETO knockdown. Since CCND2 forms a complex with the early G1 CDK4 and 6, we examined the impact of Palbociclib, a CDK4/6-specific inhibitor, on leukaemic propagation. Interestingly, prolonged treatment of Palbociclib not only caused a G1 arrest, but also induced apoptosis associated with an overall decline in cell numbers. Oral gavaging of Palbociclib in mice transplanted with leukaemic cells expressing the truncated RUNX1/ETO9A splice variant resulted in a very substantial increase in the median survival.

Conclusion: Taken together, these data show the dependence of t(8;21) AML on CCND2 expression and identify new non-genotoxic treatment opportunities for this AML subtype.