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A Novel Serine-dependent Proteolytic Activity Is Responsible for Truncated Signal Transducer and Activator of Transcription Proteins in Acute Myeloid Leukemia Blasts¹

Leukemia Section, Department of Medicine, Biopolymer Facility and Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York 14263

Hematopoietic cytokine receptor signaling involves activation of signal transducer and activator of transcription (STAT) proteins that are thought to control cellular differentiation. Truncated STAT isoforms (ß forms, rather than the normal forms) have been described and found to block the normal signaling function of the isoforms. We recently demonstrated STATß isoforms in bone marrow samples from 21 of 27 (78%) acute myeloid leukemia (AML) patients. We sought to determine the mechanism by which the STATß forms were generated. Samples from eight newly diagnosed AML patients were studied; four expressed predominantly STAT, and four expressed predominantly STATß. The reverse transcription-PCR generated identical products in the two groups, suggesting that alternate mRNA splicing is not responsible for the genesis of STATß. Extracts from cells expressing predominantly STATß incubated with cell extracts from the MO7E cell line, which expresses predominantly STAT, caused a decrease of the isoforms and an increase of the ß isoforms, suggesting the presence of proteolytic activity. This proteolytic activity was: (a) specific for STAT3 and STAT5, but not for STAT6; (b) serine dependent; (c) equally present in nuclear and cytoplasmic fractions of the leukemic blasts; and (d) different than the activity detected in a murine hematopoietic cell line. The cleaved ß isoforms retained their DNA-binding activity. Because expression of truncated STATs may be involved in blocking differentiation of AML blasts, elucidation of the regulation of the proteolytic activity may contribute to our understanding of leukemogenesis.

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