Deregulated E2F-1 blocks terminal differentiation and loss of leukemogenicity of M1 myeloblastic leukemia cells without abrogating induction of p15(INK4B) and p16(INK4A)

The transcription factor E2F-1 has been postulated to play a crucial role i n the control of cell cycle progression because of its ability to be bound and regulated by the retinoblastoma gene product (pRb). Exogenous expressio n of E2F-1, under growth restrictive conditions, was shown to result in p53 -dependent programmed cell death. The consequences of deregulated expressio n of E2F-1 on terminal differentiation of hematopoietic cells in the absenc e of E2F-1-mediated apoptosis, as well as mechanistic insights into how der egulated E2F-1 may affect terminal differentiation, have not been establish ed. The autonomously proliferating M1 myeloblastic leukemia cell line, whic h is null for p53 expression and can be induced by interleukin-6 (IL-6) to undergo terminal macrophage differentiation with concomitant loss of leukem ogenicity, provides a particularly attractive model system to address these issues. Deregulated and continued expression of E2F-1 blocked the IL-6-ind uced terminal differentiation program at an early blast stage, giving rise to immature cells, which continued to proliferate without undergoing apopto sis and retained their leukemogenic phenotype, Although E2F-1 blocked IL-6- mediated terminal differentiation and its associated growth arrest, it did not prevent the rapid induction of both p15(INK4B) and p16(INK4A), inhibiti on of cdk4 kinase activity, and subsequent hypophosphorylation of pRb, The results obtained imply that genetic alterations that both impair p53 functi on and deregulate E2F-1 expression may render hematopoietic cells refractor y to the induction of differentiation and are, thereby, likely to play a ma jor role in the progression of leukemias. (C) 2000 by The American Society of Hematology.