Abstract 2548: P57Kip2 restrains the stress response of hematopoietic stem cells and its absence leads to chemotherapy resistance

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC The cyclin-dependent kinase inhibitor P57Kip2 (Cdkn1c, p57) is a tumor suppressor gene with strong differential expression in both human and murine hematopoietic stem cells (HSC). P57 serves essential roles during embryogenesis, functioning in tissue-specific developmental programs to coordinate proliferation, differentiation and apoptosis. We have identified P57 as an early transcriptional target of the tumor suppressor TGFβ which is required for TGFβ-induced cytostasis of human CD34+ hematopoietic progenitor/stem cells; functions that provide a mechanistic basis for its expression being silenced in many aggressive human myeloid and lymphoid malignancies. To understand the role of P57 in HSC function, we used an engineered mouse strain deficient in P57. Using limiting-dilution HSC transplantation, the gold-standard assay with which to enumerate HSCs, we found that the fetal livers of p57-null mice have ∼4-fold fewer HSCs than their wild-type littermate controls. When we transplanted wt recipient mice with a mixture of p57-wt and p57-null fetal liver mononuclear cells (FLMC), we found that the p57-null hematopoietic cells were underrepresented in the blood of the recipient animals at steady-state. Both the limiting-dilution and competitive repopulation experiments indicate that the absence of p57 compromises HSC development. Strikingly, despite this quantitative deficit, we found that p57-null HSCs are qualitatively superior to p57-wt HSCs. Using serial transplantation, an assay of in vivo HSC self-renewal, we found that p57-null HSCs can be transplanted for two generations beyond which p57-wt HSCs are exhausted and unable to reconstitute hematopoiesis in the recipient animals. This result demonstrates under the tonic strain of serial transplantation, p57 normally serves to restrain HSC self-renewal. Importantly, mice with p57-null hematopoiesis are less sensitive to myelotoxic stress induced by the chemotherapeutics, 5-Fluorouracil (5FU) and cytarabine and have a shallower and shorter nadir following such treatment. Mice with p57-null hematopoiesis also recovered more briskly to the haemolytic agent phenylhydrazine suggesting that p57 serves a critical function restraining the stress-response of hematopoisis. When we administered 5FU to mice transplanted with mixtures of p57-null and p57-wt HSCs, we found that p57-null hematopoiesis contributed disproportionately to hematopoietic recovery and that this enhanced competition was durable. In composite, our findings reveal a novel role of p57 to restrain HSC self-renewal during periods of hematopoietic stress. These results suggest that cells deficient in p57 have an advantage over p57-expressing cells only after hematopoietic stress suggesting that silenced p57 expression can serve to promote malignant hematopoiesis at the expense of normal hematopoiesis and may contribute to chemotherapy resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2548.