Functional analysis of the leukemia protein ELL: Evidence for a role in the regulation of cell growth and survival

The ELL gene encodes an RNA polymerase II transcription factor that frequen tly undergoes translocation with the MLL gene in acute human myeloid leukem ia. Here, we report that ELL can regulate cell proliferation and survival. In order to better understand the physiological role of the ELL protein, we have developed an ELL-inducible cell line. Cells expressing ELL were unifo rmly inhibited for growth by a loss of the G(1) population and an increase in the G(2)/M population. This decrease in cell growth is followed by the c ondensation of chromosomal DNA, activation of caspase 3, poly(ADP ribose) p olymerase cleavage, and an increase in sub-G(1) population, which are all i ndicators of the process of programmed cell death. In support of the role o f ELL in induction of cell death, expression of an ELL antisense RNA or add ition of the caspase inhibitor ZVAD-fmk results in a reversal of ELL-mediat ed death. We have also demonstrated that the C-terminal domain of ELL, whic h is conserved among the ELL family of proteins that we have cloned (ELL, E LL2, and ELL3), is required for ELL's activity in the regulation of cell gr owth. These novel results indicate that ELL can regulate cell growth and su rvival and may explain how ELL translocations result in the development of human malignancies.