STAT3ß is a tumor suppressor in acute myeloid leukemia

Signal transducer and activator of transcription 3 (STAT3), an important multifunctional regulator of transcription, is expressed in two alternatively spliced isoforms, STAT3a and truncated STAT3ß. While STAT3ß was postulated to act as a dominant negative form of STAT3a, it has been shown to have various STAT3a-independent regulatory functions. Recently, STAT3ß gained attention as a powerful anti-tumorigenic molecule in cancer. Deregulated STAT3 signaling is frequently observed in hematological malignancies, however, the role of STAT3ß in acute myeloid leukemia (AML) remains elusive. We analyzed a cohort of AML patients for the STAT3ß/a mRNA expression ratio and observed that a higher STAT3ß/a ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3ß in leukemia we engineered a transgenic mouse allowing for balanced Stat3ß expression. Transgenic Stat3ß expression resulted in enhanced disease latency in PTEN- and MLL-AF9-dependent mouse models of AML. In conclusion, we demonstrate that STAT3ß plays an essential tumor suppressor role in AML and its mRNA expression acts as an important prognostic tool in AML patients. Overall design: RNA-seq of sorted Venus + BM cells ( Stat3ß TG ) and wt, 3 replicates each