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CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) is a regulator of the acetyltransferase CBP/p300 and elevated CITED2 levels are shown in a number of acute myeloid leukemia (AML). To study the  in vivo  role of CITED2 in AML maintenance, AML cells were transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. Mice transplanted with CITED2-knockdown AML cells ( n =4) had a significantly longer survival compared to mice transplanted with control AML cells ( P <0.02).  In vitro , the reduction of CITED2 resulted in increased p53-mediated apoptosis and  CDKN1A  expression, whereas  BCL2  levels were reduced. The activation of p53 upon CITED2 knockdown is not a direct consequence of increased CBP/p300-activity towards p53, since no increased formation of CBP/p300/p53 complexes was demonstrated and inhibition of CBP/p300-activity could not rescue the phenotype of CITED2-deficient cells. Instead, loss of CITED2 had an inhibitory effect on the AKT-signaling pathway, which was indicated by decreased levels of phosphorylated AKT and altered expression of the AKT-pathway regulators  PHLDA3  and  SOX4 . Notably, simultaneous upregulation of  BCL2  or downregulation of the p53-target gene  PHLDA3  rescued the apoptotic phenotype in CITED2-knockdown cells. Furthermore, knockdown of CITED2 led to a decreased interaction of p53 with its inhibitor MDM2, which results in increased amounts of total p53 protein. In summary, our data indicate that CITED2 functions in pathways regulating p53 activity and therefore represents an interesting target for AML therapy, since  de novo  AML cases are characterized by an inactivation of the p53 pathway or deregulation of apoptosis-related genes.

CITED2 affects leukemic cell survival by interfering with p53 activation