Rpl22 deficiency predisposes to leukemic transformation by blunting DNA damage responses (HEM2P.263)

Abstract

Abstract Mutations that impair DNA repair mechanisms lead to accumulation of DNA damage within hematopoietic stem cells (HSC), resulting in their functional exhaustion or development into leukemic stem cells (LSC). Surprising, we have found that one such mutation in the ribosomal protein Rpl22 is able to predispose to leukemic transformation and this appears to involve impaired responses to DNA damage. Indeed, Rpl22-defiicency renders lineage negative Sca-1+, c-kit+ (LSK) hematopoietic progenitors resistant to killing by the DNA-damaging agent 5-fluorouricil (5FU), which is used to treat a variety of malignancies. Interestingly, while 5FU treatment increases γH2AX phosphorylation in Rpl22-deficeint LSK, indicating that cellular DNA has been damaged, these cells fail to induce transcriptionally active p53 because of a defect in their DNA-damage response signaling. This leads to an accumulation of LSK harboring damaged DNA, which we hypothesize predisposes them to transformation. Consistent with this viewpoint, we have found that Rpl22-/- LSK do exhibit an enhanced predisposition to transformation by the oncogenic function of MLL-AF9 in mouse models. This also appears to be true in human cancer patients, since AML patients that express less Rpl22 exhibit reduced survival. Taken together, these data support our hypothesis that Rpl22-deficiency impairs the activation of p53 in response to DNA damage and this predisposes cells to transformation and more aggressive leukemias.