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Gewählte Publikation:

SHR Neuro Krebs Kardio Lipid

Sadovnik, I; Hoelbl-Kovacic, A; Herrmann, H; Eisenwort, G; Cerny-Reiterer, S; Warsch, W; Hoermann, G; Greiner, G; Blatt, K; Peter, B; Stefanzl, G; Berger, D; Bilban, M; Herndlhofer, S; Sill, H; Sperr, WR; Streubel, B; Mannhalter, C; Holyoake, TL; Sexl, V; Valent, P.
Identification of CD25 as STAT5-Dependent Growth Regulator of Leukemic Stem Cells in Ph+ CML.
Clin Cancer Res. 2016; 22(8):2051-2061 [OPEN ACCESS]
Web of Science PubMed PUBMED Central FullText FullText_MUG

 

Autor/innen der Med Uni Graz:
Sill Heinz
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Number of Figures: 5
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Abstract:
In chronic myelogenous leukemia (CML), leukemic stem cells (LSC) represent a critical target of therapy. However, little is known about markers and targets expressed by LSCs. The aim of this project was to identify novel relevant markers of CML LSCs. CML LSCs were examined by flow cytometry, qPCR, and various bioassays. In addition, we examined the multipotent CD25(+)CML cell line KU812. In contrast to normal hematopoietic stem cells, CD34(+)/CD38(-)CML LSCs expressed the IL-2 receptor alpha chain, IL-2RA (CD25). STAT5 was found to induce expression of CD25 in Lin(-)/Sca-1(+)/Kit(+)stem cells in C57Bl/6 mice. Correspondingly, shRNA-induced STAT5 depletion resulted in decreased CD25 expression in KU812 cells. Moreover, the BCR/ABL1 inhibitors nilotinib and ponatinib were found to decrease STAT5 activity and CD25 expression in KU812 cells and primary CML LSCs. A CD25-targeting shRNA was found to augment proliferation of KU812 cellsin vitroand their engraftmentin vivoin NOD/SCID-IL-2Rγ(-/-)mice. In drug-screening experiments, the PI3K/mTOR blocker BEZ235 promoted the expression of STAT5 and CD25 in CML cells. Finally, we found that BEZ235 produces synergistic antineoplastic effects on CML cells when applied in combination with nilotinib or ponatinib. CD25 is a novel STAT5-dependent marker of CML LSCs and may be useful for LSC detection and LSC isolation in clinical practice and basic science. Moreover, CD25 serves as a growth regulator of CML LSCs, which may have biologic and clinical implications and may pave the way for the development of new more effective LSC-eradicating treatment strategies in CML. ©2015 American Association for Cancer Research.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Antineoplastic Agents - pharmacology
Biomarkers -
Cell Line, Tumor -
Disease Models, Animal -
Drug Design -
Drug Synergism -
Gene Expression -
Gene Expression Regulation, Leukemic - drug effects
Genes, abl -
Heterografts -
Humans -
Immunophenotyping -
Interleukin-2 Receptor alpha Subunit - genetics
Interleukin-2 Receptor alpha Subunit - metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Mice -
Neoplastic Stem Cells - metabolism
Protein Kinase Inhibitors - pharmacology
STAT5 Transcription Factor - genetics
STAT5 Transcription Factor - metabolism

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