How can p53 induce differentiation of leukemic cells?

Sammanfattning: The terminal differentiation of leukemic cells is closely connected to their death. The concept of differentiation therapy originates from the idea that forced maturation of leukemic cells could induce cell death without the side-effects that are provoked by ordinary chemotherapy. The tumour suppressor protein p53 is a transcription factor, and can induce cell cycle arrest and apoptosis of malignant cells. Importantly, p53 is also known to induce differentiation in many different tissues including leukemic cells. Thus, to restore p53-dependent pathways for differentiation is an attractive approach in the development of a functional differentiation therapy. However, further knowledge is necessary in order to realise such a concept. Therefore, the aim of this thesis was to better understand the pathways for p53-mediated differentiation of leukemic cells. To that end, a temperature inducible p53 mutant (ptsp53) was overexpressed in erythroleukemic K562 cells and monoblastic U-937-4 cells. We show that induced expression of p53 facilitates erythroid but not megakaryocytoid differentiation. Moreover, p53 can induce differentiation of U-937-4 cells in spite of inhibition of p53-mediated apoptosis as mediated by bcl-2. Also, the amount of active p53 seems to determine whether p53 will induce apoptosis or differentiation. In addition, p53-mediated differentiation depends on the transcription regulatory capacity of p53, but the p53 target gene p21 does not seem to be the key molecule mediating p53-induced differentiation. The Wilms tumour protein WT1 binds to p53, modulating its functions. Our data demonstrate that WT1 interferes with the differentiation of monoblastic U-937-4 cells, suggesting that WT1 could have a role in the differentiation block of acute leukemia. In conclusion, our data speak in favour of development of differentiation therapy based on p53-dependent differentiation pathways.