Functional interaction between TP53 and del(5q). (A) Effects of RPS14 haploinsufficiency on TP53 protein levels. In this model, haploinsufficient RPS14 results in an increase in ribosome-free RPL11, which by competing with TP53 for binding MDM2, an E3 ubiquitin ligase that also targets p53 for destruction, inhibits TP53 destruction in the proteasome, leading to an elevated TP53 level and an enhanced TP53-mediated apoptosis of erythroid progenitors.^101,102  Protein levels corresponding to diploid and haploid status of RPS14 are indicated by solid and broken lines, respectively. (B) Effects of haploinsufficiency of CSKN2A on Wnt signaling and TP53 activation and their implication in the mechanism behind the high response of del(5q) clones to lenalidomide. Haploinsufficiency of RPS14 and CSKN2A induced TP53 activation, leading to enhanced apoptosis of del(5q) clones, while haploinsufficient CSKN2A results in the activation of Wnt signaling and cell proliferation. Apoptosis of del(5q) clones, particularly that induced by lenalidomide, critically depends on intact TP53, which explains the strong correlation between del(5q) and mutated TP53.