The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients

Show full item record



Permalink

http://hdl.handle.net/10138/198911

Citation

Schubert , C , Chatain , N , Braunschweig , T , Schemionek , M , Feldberg , K , Hoffmann , M , Dufva , O , Mustjoki , S , Bruemmendorf , T H & Koschmieder , S 2017 , ' The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients ' , Oncotarget , vol. 8 , no. 21 , pp. 34736-34749 . https://doi.org/10.18632/oncotarget.16152

Title: The SCLtTAxBCR-ABL transgenic mouse model closely reflects the differential effects of dasatinib on normal and malignant hematopoiesis in chronic phase-CML patients
Author: Schubert, Claudia; Chatain, Nicolas; Braunschweig, Till; Schemionek, Mirle; Feldberg, Kristina; Hoffmann, Melanie; Dufva, Olli; Mustjoki, Satu; Bruemmendorf, Tim H.; Koschmieder, Steffen
Contributor: University of Helsinki, Medicum
University of Helsinki, Medicum
Date: 2017-05-23
Language: eng
Number of pages: 14
Belongs to series: Oncotarget
ISSN: 1949-2553
URI: http://hdl.handle.net/10138/198911
Abstract: The second generation tyrosine kinase inhibitor (TKI) dasatinib is a clinically approved drug for chronic myeloid leukemia (CML) as well as Ph+ acute lymphoblastic leukemia. In addition to its antileukemic effects, dasatinib was shown to impact on normal hematopoiesis and cells of the immune system. Due to the fact that the murine in vivo studies so far have not been performed in a chronic-phase CML model under steady-state conditions, our aim was to study the hematopoietic effects of dasatinib (20 mg/kg p.o.) in BCR-ABL expressing SCLtTAxBCR-ABL double transgenic (dtg) mice. Dasatinib robustly antagonized the CML phenotype in vivo in our transgenic mouse model, and this effect included both mature and immature cell populations. However, similar to patients with CML, the fraction of Lin(neg)Sca-1(+)KIT(+)CD48(neg)CD150(+) hematopoietic stem cells was not reduced by dasatinib treatment, suggesting that these cells are not oncogene-addicted. Moreover, we observed differential effects of dasatinib in these animals as compared to wild-type (wt) animals: while granulocytes were significantly reduced in dtg animals, they were increased in wt mice. And Ter119(+) erythrocytic and B220(+) B cells were increased in dtg mice but decreased in wt mice. Finally, while dasatinib induced a shift from CD49b/NK1.1 positive NK cells from the bone marrow to the spleen in wt animals, there was no change in dtg mice. In conclusion, the present mouse model provides a useful tool to study mechanisms of TKI resistance and dasatinib-associated beneficial effects and adverse events.
Subject: CML
BCR-ABL
dasatinib
mouse model
transgenic
CHRONIC MYELOID-LEUKEMIA
CHRONIC MYELOGENOUS LEUKEMIA
TYROSINE KINASE INHIBITOR
STEM-CELLS
NK-CELLS
IMATINIB
EXPANSION
THERAPY
MICE
QUIESCENT
3122 Cancers
1182 Biochemistry, cell and molecular biology
Rights:


Files in this item

Total number of downloads: Loading...

Files Size Format View
16152_257593_2_PB.pdf 4.774Mb PDF View/Open

This item appears in the following Collection(s)

Show full item record