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STAT3? is a tumor suppressor in acute myeloid leukemia.

ABSTRACT: Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3? and STAT3?. Although truncated STAT3? was originally postulated to act as a dominant-negative form of STAT3?, it has been shown to have various STAT3?-independent regulatory functions. Recently, STAT3? 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? in AML remains elusive. Therefore, we analyzed the STAT3?/? messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3?/? mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3? in AML, we engineered a transgenic mouse allowing for balanced Stat3? expression. Transgenic Stat3? 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? 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? plays an essential tumor-suppressive role in AML.

SUBMITTER: Aigner P

PROVIDER: S-EPMC6616266 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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STAT3β is a tumor suppressor in acute myeloid leukemia.

Aigner Petra P Mizutani Tatsuaki T Horvath Jaqueline J Eder Thomas T Heber Stefan S Lind Karin K Just Valentin V Moll Herwig P HP Yeroslaviz Assa A Fischer Michael J M MJM Kenner Lukas L Győrffy Balázs B Sill Heinz H Grebien Florian F Moriggl Richard R Casanova Emilio E Stoiber Dagmar D

Blood advances 20190701 13

Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3α and STAT3β. Although truncated STAT3β was originally postulated to act as a dominant-negative form of STAT3α, it has been shown to have various STAT3α-independent regulatory functions. Recently, STAT3β gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3β in AML remains el ...[more]

PMID: 31270081

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Project description:BackgroundDysregulation of miRNAs that can act as tumor suppressors or oncogenes can result in tumorigenesis. Previously we demonstrated that miR-199b was significantly downregulated in acute myeloid leukemia (AML) and targets podocalyxin and discoidin domain receptor 1. Herein we investigated the functional role of miR-199b in AML and its prognostic implications.MethodsMajor approaches include transduction of hematopoietic stem cells and bone marrow transplantation, analyses of blood lineages, histone deacetylases (HDAC) inhibitors, and molecular and clinical data analyses of AML patients using The Cancer Genome Atlas (TCGA).ResultsWe first examined the relative miR-199b expression in steady state hematopoiesis and showed CD33(+) myeloid progenitors had the highest miR-199b expression. Further, silencing of miR-199b in CD34(+) cells resulted in significant increases in CFU-GM colonies. Via TCGA we analyzed the molecular and clinical characteristics of 166 AML cases to investigate a prognostic role for miR-199b. The Kaplan-Meier curves for high and low expression values of miR-199b and the observed distribution of miRNA expression revealed the highly expressed group had significantly better survival outcomes (p < 0.016, log rank test). Additionally, there was significant difference between miR-199b expression across the AML subtypes with particularly low expression found in the FAB-M5 subtype. Furthermore, FAB-M5 subtype showed a poor prognosis with a 1-year survival rate of only 25 %, compared with 51 % survival in the overall sample (p < 0.024). Furthermore, significant inverse correlation of HoxA7 and HoxB6 expression with miR-199b was observed in FAB-M5 AML patients. Molecular mutations were analyzed among miR-199b high and low AML cases. Significant correlations in terms of association and survival outcomes were observed for NPMc and IDH1 mutations. Treatment of THP-1 cells (represents M5-subtype) with HDAC inhibitors AR-42, Panobinostat, or Decitabine showed miR-199b expression was significantly elevated upon AR-42 and Panobinostat treatment. To further understand the hematopathological consequences of decreased miR-199b, we employed a bone-marrow transduce/transplant (BMT) mouse model. Interestingly, in vivo miR-199b silencing per-se in HSCs did not result in profound perturbations.ConclusionsLoss of miR-199b can lead to myeloproliferation while HDAC inhibitors restore miR-199b expression and promote apoptosis. Low miR-199b in AML patients correlates with worse overall survival and has prognostic significance for FAB-M5 subtype.

Dataset Information

STAT3? is a tumor suppressor in acute myeloid leukemia.

Publications

STAT3β is a tumor suppressor in acute myeloid leukemia.

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