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Hyperactivated AKT ...
Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosis
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- Tang, Yanjuan (författare)
- Linköpings universitet,Institutionen för klinisk och experimentell medicin,Hälsouniversitetet
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- Halvarsson, Camilla (författare)
- Linköpings universitet,Institutionen för klinisk och experimentell medicin,Hälsouniversitetet
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- Nordigården, Amanda (författare)
- Linköpings universitet,Cellbiologi,Hälsouniversitetet
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- Åhsberg, Josefine (författare)
- Linköpings universitet,Experimentell hematologi,Hälsouniversitetet
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- Wong, Wan Man (författare)
- Lund Strategic Center for Stem Cell Biology and Cell Therapy, Lund University, Lund, Sweden
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- Jönsson, Jan-Ingvar (författare)
- Linköpings universitet,Experimentell hematologi,Hälsouniversitetet
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(creator_code:org_t)
- Engelska.
- Relaterad länk:
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https://urn.kb.se/re...
Abstract
Ämnesord
Stäng
- The PI3K-AKT signaling pathway plays an important role in cell growth and metabolism. Increased AKT activity is frequently seen in patients with acute myeloid leukemia (AML), providing leukemic cells with both growth-promoting and survival signals involved in the transformation process. In AML up to 30% of all patients carry activating mutations in the tyrosine kinase receptor FLT3, leading to activation of the PI3K/AKT pathway as well as STAT5. Here, we investigated the effect of hyperactivated AKT (myristylated AKT) by retroviral transfer to hematopoietic progenitor cells coexpressing STAT5, FLT3-ITD, or antiapoptotic Bcl-2. AKT was unable to relieve cytokine-dependence. Surprisingly, uncontrolled AKT activity was linked to accumulation of cells in the G0 stage of the cell cycle and increased cell numbers became apoptotic. Hyperactivated AKT was incompatible with STAT5-driven proliferation and triggered apoptosis. The same was true also in FLT3-ITDexpressing progenitor cells of transgenic mice. Transplantable hematopoietic stem cells of wildtype and Bcl-2 transgenic mice were impaired in their engraftment ability to recipient mice when expressing hyperactivated AKT. This was linked to AKT-mediated pro-apoptotic functions and not due to effects on homing or migration. Cells expressing hyperactivated AKT displayed higher levels of reactive oxygen species. However, the addition of the antioxidant N-acetyl-L-lysine significantly reduced apoptosis. Taken together, the results indicate that constitutive AKT activity is incompatible with the growth- and survivalpromoting ability of FLT3-ITD and its downstream targets. These findings may provide a novel tool to intervene with AKT activity in leukemia.
Nyckelord
- Hematopoiesis
- transplantation
- oncogenes
- AKT
- STAT5
- FLT3-ITD
- Bcl-2
- apoptosis
Publikations- och innehållstyp
- vet (ämneskategori)
- ovr (ämneskategori)