On the Role of the Tumor Suppressor p53 in Leukemic Cell Differentiation

Abstract: Leukemic cells suffer from an impaired ability to differentiate due to inherited or acquired genetic lesions. These genetic changes can sometimes be bypassed with various compounds both in vitro, and, more rarely, in vivo, thus inducing terminal differentiation of the leukemic cells. Differentiation of both leukemic and normal hematopoietic cells is believed to be intimately coupled to cell cycle regulation and proliferation. The aim was therefore to increase the propensity of leukemic cells towards differentiation by overexpressing cell cycle active tumor suppressor genes, and to identify genes essential for differentiation pathways in these cells. The results show that the retinoblastoma protein, an important cell cycle regulating and tumor suppressor molecule, is necessary for induction of differentiation of certain leukemic cells with some agents. Furthermore, the mechanisms of differentiation do not merely depend on cell cycle regulation. The tumor suppressor protein p53 is another pivotal cell cycle regulator which halts the cell cycle in the G1-phase mainly by controlling the activity of the retinoblastoma protein. The present study demonstrates that it is possible to dispose leukemic cells for terminal differentiation by increasing the intracellular concentration of p53 through overexpression of the p53 gene. This was evidenced both by signs of terminal differentiation in response to p53 alone and by an increased sensitivity of p53-expressing cells towards a number of differentiation-inducing compounds. The mechanisms of p53-mediated differentiation do not necessarily rely on p53´s ability to regulate the activity of the retinoblastoma protein and cell cycle progression. Furthermore, p53-independent terminal differentiation is achievable in growth arrested cells in the G1-phase of the cell cycle. G1-phase cell cycle arrest by itself does however not seem to be sufficient to induce any signs of differentiation. Therefore, it is proposed that differentiation and cell cycle regulation are two separately regulated processes.