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Hyperactivated AKT is incompatible with survival when coexpressed with additional oncogenes and drives hematopoietic stem and progenitor cells to cell cycle inhibition and apoptosis
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology. Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
Hematopoiesis, transplantation, oncogenes, AKT, STAT5, FLT3-ITD, Bcl-2, apoptosis
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-88201OAI: oai:DiVA.org:liu-88201DiVA: diva2:602073
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2013-01-31
In thesis
1. The FLT3 Tyrosine Kinase in Leukemia: Deciphering the Downstream Signaling Events and Drug-Escape Mechanisms
Open this publication in new window or tab >>The FLT3 Tyrosine Kinase in Leukemia: Deciphering the Downstream Signaling Events and Drug-Escape Mechanisms
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Acute myeloid leukemia (AML) is a severe disease, which originates in blood-forming cells. Although major advances in understanding the biology of AML, the majority of patients eventually succumb to the disease. The tyrosine kinase receptor FLT3 has become an attractive therapeutic target AML for two major reasons; 1) It is one of the most frequently mutated genes in AML (about 30%). 2) Most of these mutations (FLT3-ITDs) correlate with an increased risk of relapse and poor overall survival. Small targeting inhibitors towards FLT3 have been designed and evaluated in clinical trials. However, the experiences from clinical trials are that drug resistance develops in a substantial number of patients. To overcome these resistance-associated problems it its important to improve the understanding of how FLT3 mutations function and how they respond to targeting drugs. This was addressed in this thesis by elucidating FLT3-ITD cell transformation mechanisms, identifying key downstream target molecules of mutated FLT3 and exploring the effect of various targeting inhibitors. The major finding of my thesis is that FLT3-targeting drugs elicit apoptosis through a FOXO3a-dependent upregulation of proapoptotic BH3-only protein Bim via inactivation of the PI3K/AKT signaling pathway. Furthermore, we have identified an interesting apoptotic mechanism, linked to increased ROS levels caused by expressing hyperactivated AKT in hematopoietic stem cells and bone marrow progenitor cells from FLT3-ITD transgenic mice. These findings are interesting from a therapeutic point of view. We have also shown that canertinib, an inhibitor of the ERBB receptor family, targets mutated FLT3 in vitro and in vivo. The irreversible binding mechanism of canertinib, as well as its multikinase activity, is attractive features. Overall, the results presented herein could provide basis for future directions in treatment of FLT3 mutant positive AML patients. Finally, we studied nine different FLT3-ITD mutations ranging in length from 6-33 amino acids. Data from this study suggest that different FLT3-ITDs may induce distinct degrees of transformation and that they respond differentially to FLT3-targeting drugs. These differences were not associated with size of the duplication but rather the mutational composition. In conclusion, this thesis explores the biologic features of FLT3 mutations and therapeutic targeting opportunities.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 69 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1355
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-88202 (URN)978-91-7519-685-5 (ISBN)
Public defence
2013-02-26, Nils Holgersalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 13:15 (Swedish)
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Supervisors
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-07-07Bibliographically approved

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Tang, YanjuanHalvarsson, CamillaNordigården, AmandaÅhsberg, JosefineJönsson, Jan-Ingvar

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