Strated that quiescent CML stem cells do not undergo apoptosis even in the presence of high-dose or more potent TK inhibitors. Moreover, seminal studies demonstrated that a quiescent population of CML stem cells with BCR-ABL kinase domain mutation that is detectable before the initiation of IM therapy gives rise to leukemic cells that persist after treatment see references [1-7,49-52]. These findings suggest that CML stem cells EPZ-5676 side effects contribute to CML persistence and disease progression. A question to be further addressed is whether ABCB1 is also regulated by the canonical Wnt pathway in CML stem cells, as this pathway has also been correlated with self-renewal. CML stem cells and normal hematopoietic stem cells (HSC) share several characteristics despite exhibiting remarkable differences. Self-renewal is an essential stem cell property, but self-renewal pathway activation has also been increasingly recognized as a hallmark of cancer. Interestingly, HSC and CML stem cells also exhibit increased levels of drug efflux-related molecules such as the product of ABCB1, Pgp and decreased levels of OCT1, a transporter involved in the uptake of IM, rendering them more resistant to drugs [53,54].Acknowledgements We thank Dra. Vivian Rumjanek (Departamento de Bioqu ica M ica, Universidade Federal do Rio de Janeiro, Brazil) for providing the Lucena cell line. This work was supported by FINEP, FAPERJ, CNPQ and INCT of Cancer Control. Author details Divis de Laborat ios CEMO, INCA, Rio de Janeiro, Brazil. 2Instituto de Biof ica Carlos Chagas Filho, PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/29045898 Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. 3Instituto de Ci cias Biom icas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.Authors’ contributions SC performed the experiments, statistical analysis and drafted the manuscript. RB participated and assisted the electrophoretic mobility shift assays and Luciferase experiments. BR participated in flow cytometry experiments. MTLCB performed immunofluorescence assays. LP and EA made substantial contributions to the study conception and design and critically revised the manuscript for intellectual content. All authors read and approved the final manuscript. Received: 27 October 2011 Accepted: 23 July 2012 Published: 23 July 2012 References 1. Jiang X, Zhao Y, Smith C, Gasparetto M, Turhan A, Eaves A, Eaves C: Chronic myeloid leukemia stem cells possess multiple unique features of resistance to BCR-ABL targeted therapies. Leukemia 2007, 21:926?35. 2. J gensen HG, Holyoake TL: Characterization of cancer stem cells in chronic myeloid leukaemia. Biochem Soc Trans 2007, 35:1347?351. 3. Radich JP, Dai H, Mao M, Oehler V, Schelter J, Druker B, Sawyers C, Shah N, Stock W, Willman CL, Friend S, Linsley PS: Gene expression changes associated with progression and response in chronic myeloid leukemia. Proc Natl Acad Sci U S A 2006, 103:2794?799. 4. Zhao C, Blum J, Chen A, Kwon HY, Jung SH, Cook JM, Lagoo A, Reya T: Loss of beta-catenin impairs the renewal of normal and CML stem cells in vivo. Cancer Cell. 2007, 12:528?41. 5. Chen Y, Peng C, Sullivan C, Li D, Li S: Critical molecular pathways in cancer stem cells of chronic myeloid leukemia. Leukemia 2010, 24:1545?554. 6. Deshpande AJ, Buske C: Knocking the Wnt out of the sails of leukemia stem cell development. Cell Stem Cell. 2007, 1:597?98. 7. Hu Y, Chen Y, Douglas L, Li S: beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCRABL-induce.
