A novel serine-dependent proteolytic activity is responsible for truncatedsignal transducer and activator of transcription proteins in acute myeloidleukemia blasts

Hematopoietic cytokine receptor signaling involves activation of signal tra nsducer and activator of transcription (STAT) proteins that are thought to control cellular differentiation. Truncated STAT isoforms (beta forms, rath er than the normal alpha forms) have been described and found to block the normal signaling function of the alpha isoforms, We recently demonstrated S TAT beta isoforms in bone marrow samples from 21 of 27 (78%) acute myeloid leukemia: (AML) patients. We sought to determine the mechanism by which the STAT beta forms were generated. Samples from eight newly diagnosed AML pat ients were studied; four expressed predominantly STAT alpha, and four expre ssed predominantly STAT beta. The reverse transcription-PCR generated ident ical products in the two groups, suggesting that alternate mRNA splicing is not responsible for the genesis of STAT beta, Extracts from cells expressi ng predominantly STAT beta incubated with cell extracts from the MO7E cell line, which expresses predominantly STAT alpha caused a decrease of the a i soforms and an increase of the beta isoforms, suggesting the presence of pr oteolytic activity. This proteolytic activity was: (a) specific for STAT3 a nd STAT5, but not for STAT6; (b) serine dependent; (c) equally present in n uclear and cytoplasmic fractions of the leukemic blasts; and (d) different than the activity detected in a murine hematopoietic cell line. The cleaved beta isoforms retained their DNA-binding activity. Because expression of t runcated STATs may be involved in blocking differentiation of AML blasts, e lucidation of the regulation of the proteolytic activity may contribute to our understanding of leukemogenesis.