STAT3β is a tumor suppressor in acute myeloid leukemia

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3 alpha and STAT3 beta. Although truncated STAT3 beta was originally postulated to act as a dominant-negative form of STAT3 alpha, it has been shown to have various STAT3 alpha-aindependent regulatory functions. Recently, STAT3 beta gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3 beta in AML remains elusive. Therefore, we analyzed the STAT3 beta/alpha messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3 beta/alpha mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3 beta in AML, we engineered a transgenic mouse allowing for balanced Stat3 beta expression. Transgenic Stat3 beta expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3 beta depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3 beta plays an essential tumor-suppressive role in AML.