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

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 LinnegSca-1+KIT+CD48negCD150+ 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.

Twenty years of evolution of CML therapy: how the treatment goal is moving from disease to patient

“…In this scenario, the settling of new animal models is the most promising approach. Many efforts led to the availability of murine CML models suitable for in vivo testing of specific TKIs, [74][75][76][77] and allowing the investigation of key players in disease development. 78 Drosophila melanogaster has been also used as an alternative CML animal model.…”

Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms

“…Several mouse models miming BCR-ABL1 driven leukemogenesis (32,33) have been established [ 28 ] both to characterize the disease and to test different therapeutic compounds, particularly the BCR-ABL1 tyrosine-kinase inhibitors (TKIs) [ 29 , 30 , 31 , 32 ]. Many efforts led to the availability of murine CML models suitable for in vivo test of specific TKIs [ 33 , 34 ], and allowing the investigation of key players in disease development [ 35 , 36 , 37 ]. Drosophila melanogaster has been used as an alternative CML animal model [ 38 , 39 ] but, at present, only one stable zebrafish model for a CML-like disease has been recently generated [ 40 ].…”