Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3a and STAT3b. Although truncated STAT3b was originally postulated to act as a dominant-negative form of STAT3a, it has been shown to have various STAT3a-independent regulatory functions. Recently, STAT3b gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3b in AML remains elusive. Therefore, we analyzed the STAT3b/a messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3b/a mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3b in AML, we engineered a transgenic mouse allowing for balanced Stat3b expression. Transgenic Stat3b 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 STAT3b 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 STAT3b plays an essential tumor-suppressive role in AML.
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