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BH3-only protein Bim more critical than Puma in tyrosine kinase inhibitor-induced apoptosis of human leukemic cells and transduced hematopoietic progenitors carrying oncogenic FLT3.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
Linköping University, Department of Clinical and Experimental Medicine, Experimental Hematology . Linköping University, Faculty of Health Sciences. (Jan-Ingvar Jönsson)
Division of Developmental Immunology, Biocenter, Innsbruck Medical University. (Andreas Villunger)
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2009 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 113, no 10, 2302-2311 p.Article in journal (Refereed) Published
Abstract [en]

Constitutively activating internal tandem duplications (ITD) of FLT3 (FMS-like tyrosine kinase 3) are the most common mutations in acute myeloid leukemia (AML) and correlate with poor prognosis. Receptor tyrosine kinase inhibitors targeting FLT3 have developed as attractive treatment options. Because relapses occur after initial responses, identification of FLT3-ITD–mediated signaling events are important to facilitate novel therapeutic interventions. Here, we have determined the growth-inhibitory and proapototic mechanisms of 2 small molecule inhibitors of FLT3, AG1295 or PKC412, in hematopoietic progenitor cells, human leukemic cell lines, and primary AML cells expressing FLT3-ITD. Inactivation of the PI3-kinase pathway, but not of Ras–mitogen-activated protein (MAP) kinase signaling, was essential to elicit cytotoxic responses. Both compounds induced up-regulation of proapoptotic BH3-only proteins Bim and Puma, and subsequent cell death. However, only silencing of Bim, or its direct transcriptional activator FOXO3a, abrogated apoptosis efficiently. Similar findings were made in bone marrow cells from gene-targeted mice lacking Bim and/or Puma infected with FLT3-ITD and treated with inhibitor, where loss of Puma only provided transient protection from apoptosis, but loss of Bim preserved clonal survival upon FLT3-ITD inhibition.

 

Place, publisher, year, edition, pages
Washington, D.C: The American Society of Hematology , 2009. Vol. 113, no 10, 2302-2311 p.
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-52728DOI: 10.1182/blood-2008-07-167023OAI: oai:DiVA.org:liu-52728DiVA: diva2:285370
Available from: 2010-01-11 Created: 2010-01-11 Last updated: 2017-12-12
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)
Opponent
Supervisors
Available from: 2013-01-31 Created: 2013-01-31 Last updated: 2017-07-07Bibliographically approved
2. Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
Open this publication in new window or tab >>Live and Let Die: Critical regulation of survival in normal and malignant hematopoietic stem and progenitor cells
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The hematopoietic stem cell (HSC) is characterized by its ability to self-renew and produce all mature blood cells throughout the life of an organism. This is tightly regulated to maintain a balance between survival, proliferation, and differentiation. The HSCs are located in specialized niches in the bone marrow thought to be low in oxygen, which is suggested to be involved in the regulation of HSC maintenance, proliferation, and migration. However, the importance of hypoxia in the stem cell niche and the molecular mechanisms involved remain fairly undefined. Another important regulator of human HSCs maintenance is the tyrosine kinase receptor FLT3, which triggers survival of HSCs and progenitor cells. Mutations in FLT3 cause constitutively active signaling. This leads to uncontrolled survival and proliferation, which can result in development of acute myeloid leukemia (AML). One of the purposes with this thesis is to investigate how survival, proliferation and self-renewal in normal HSCs are affected by hypoxia. To study this, we used both in vitro and in vivo models with isolated Lineage-Sca-1+Kit+ (LSK) and CD34-Flt3-LSK cells from mouse bone marrow. We found that hypoxia maintained an immature phenotype. In addition, hypoxia decreased proliferation and induced cell cycle arrest, which is the signature of HSCs with long term multipotential capacity. A dormant state of HSCs is suggested to be critical for protecting and preventing depletion of the stem cell pool. Furthermore, we observed that hypoxia rescues HSCs from oxidative stress-induced cell death, implicating that hypoxia is important in the bone marrow niche to limit reactive oxidative species (ROS) production and give life-long protection of HSCs. Another focus in this thesis is to investigate downstream pathways involved in tyrosine kinase inhibitor-induced cell death of primary AML cells and cell lines expressing mutated FLT3. Our results demonstrate an important role of the PI3K/AKT pathway to mediate survival signals from FLT3. We found FoxO3a and its target gene Bim to be key players of apoptosis in cells carrying oncogenic FLT3 after treatment with tyrosine kinase inhibitors. In conclusion, this thesis highlights hypoxic-mediated regulation of normal HSCs maintenance and critical effectors of apoptosis in leukemic cells expressing mutated FLT3.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 93 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1160
Keyword
hematopoietic stem cells, hypoxia, self-renewal, survival, acute myeloid leukemia, FLT3
National Category
Biochemistry and Molecular Biology Hematology
Identifiers
urn:nbn:se:liu:diva-52932 (URN)978-91-7393-470-1 (ISBN)
Public defence
2009-12-11, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Note

On the day of the defence date the title of article II was "Hypoxia, via hypoxia-inducible factor (HIF)-1, mediates low cell cycle activity and preserves the engraftment potential of mouse hematopoietic stem cells" and one of the authors is no longer included in the article.

Available from: 2010-01-19 Created: 2010-01-13 Last updated: 2017-01-12Bibliographically approved

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Nordigården, AmandaEliasson, PernillaJönsson, Jan-Ingvar

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