The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells
Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in...
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2025-06-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/12117 |
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| author | Kellen B. Gil Jamie Borg Rosana Moreira Pereira Anagha Inguva-Sheth Geovana Araujo Jeremy Rahkola William Showers Abby Grier Angelo D’Alessandro Clayton Smith Christine McMahon Daniel A. Pollyea Austin E. Gillen Maria L. Amaya |
| author_facet | Kellen B. Gil Jamie Borg Rosana Moreira Pereira Anagha Inguva-Sheth Geovana Araujo Jeremy Rahkola William Showers Abby Grier Angelo D’Alessandro Clayton Smith Christine McMahon Daniel A. Pollyea Austin E. Gillen Maria L. Amaya |
| author_sort | Kellen B. Gil |
| collection | DOAJ |
| description |
Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3’s mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.
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| format | Article |
| id | doaj-art-236148d4ad9c4343bd9fe4f92c8a5191 |
| institution | OA Journals |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-236148d4ad9c4343bd9fe4f92c8a51912025-08-20T02:37:05ZengFerrata Storti FoundationHaematologica0390-60781592-87212025-06-01999110.3324/haematol.2025.287352The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cellsKellen B. Gil0Jamie Borg1Rosana Moreira Pereira2Anagha Inguva-Sheth3Geovana Araujo4Jeremy Rahkola5William Showers6Abby Grier7Angelo D’Alessandro8Clayton Smith9Christine McMahon10Daniel A. Pollyea11Austin E. Gillen12Maria L. Amaya13Department of Internal Medicine, University of Colorado School of MedicineDenver Research InstituteDivision of Hematology, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical CampusResearch Department, Rocky Mountain Regional VA Medical CenterDivision of Hematology, University of Colorado Anschutz Medical CampusDepartment of Medicine, Case Western University, Cleveland, OHDepartment of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical CampusDivision of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO; Research Department, Rocky Mountain Regional VA Medical CenterDivision of Hematology, University of Colorado Anschutz Medical Campus, Aurora, CO; Research Department, Rocky Mountain Regional VA Medical Center Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3’s mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML. https://haematologica.org/article/view/12117 |
| spellingShingle | Kellen B. Gil Jamie Borg Rosana Moreira Pereira Anagha Inguva-Sheth Geovana Araujo Jeremy Rahkola William Showers Abby Grier Angelo D’Alessandro Clayton Smith Christine McMahon Daniel A. Pollyea Austin E. Gillen Maria L. Amaya The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells Haematologica |
| title | The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| title_full | The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| title_fullStr | The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| title_full_unstemmed | The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| title_short | The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| title_sort | stat3 vdac1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells |
| url | https://haematologica.org/article/view/12117 |
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