Potential role of Wnt/β-catenin signaling in blastic transformation of chronic myeloid leukemia: cross talk between β-catenin and BCR-ABL
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Chronic myeloid leukemia (CML) results from malignant transformation of hematopoietic stem cells induced by the BCR-ABL oncogene. Transformation from chronic to blastic phase is the lethal step in CML. Leukemic stem cells (LSCs) are the basic reason for blastic transformation. It has been shown that Wnt/β-catenin signaling contributes to the self-renewal capacity and proliferation of LSCs in CML. However, the role of Wnt/β-catenin signaling in blastic transformation of CML is still obscure. Here, we explored the relationship between BCR-ABL and β-catenin signaling in vitro and in vivo. We found that BCR-ABL stimulated β-catenin via activation of PI3K/AKT signaling in blastic phase CML cells. Inhibition of the kinase activity of BCR-ABL, PI3K, or AKT decreased the level of β-catenin in both K562 cells and a CML mouse model and suppressed the transcription of downstream target genes (c-myc and cyclin D1). In addition, inhibition of the BCR-ABL/PI3K/AKT pathway delayed the disease progression in the CML mouse model. To further explore the role of β-catenin in the self-renewal and survival of CML LSCs, we established a secondary transplantation CML mouse model. Our data revealed that inhibition of the BCR-ABL/PI3K/AKT pathway reduced the tumor-initiating ability of K562 cells, decreased leukemia cell infiltration into peripheral blood and bone marrow, and prolonged the survival of mice. In conclusion, our data indicate a close relationship between β-catenin and BCR-ABL/PI3K/AKT in blastic phase CML. β-Catenin inhibition may be of therapeutic value by targeting LSCs in combination with a tyrosine kinase inhibitor, which may delay blastic transformation of CML.
Keywordsβ-Catenin BCR-ABL PI3K/AKT Chronic myeloid leukemia Blastic transformation
This work was funded by the Natural Science Foundation of CQ CSTC (cstc2012jjA10013) to Jing Hu and the Special Fund of Chongqing Key Laboratory (CSTC) (2012-2015) to Jing Hu.
Compliance with ethical standards
This study was authorized by the Human Ethics Committee of Chongqing Medical University. All participants provided written informed consent.
The ethical standards includes:
1. Whether the project should be carried out with experimental animal experiment. Whether it could be done with computer simulation, cell culture or lower animals instead of higher animal.
2. Whether the animals used in this experiment are suitable. Whether the number of animals could be reduced through improved design or high quality animals.
3. Whether animals are treated ethically through improving experiment method, adjusting experimental observation index, optimizing the experiment scheme.
4. Whether animal welfare measures are implemented.
All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.
Conflicts of interest
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