Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm resulting from clonal expansion of hematopoietic stem cells positive for the Philadelphia chromosome. The CML pathogenesis is associated with expression of the BCR–ABL1 oncogene, which encodes the Bcr–Abl protein with tyrosine kinase activity, promoting the leukemic cell exacerbated myeloproliferation and resistance to apoptosis. CML patients are usually treated with tyrosine kinase inhibitors (TKI), but some of them acquire resistance or are refractory to TKI. Thus, it is still relevant to elucidate the CML pathogenesis and seek new therapeutic targets, such as the Hippo signaling pathway and cell cycle regulatory genes from the Aurora kinase family. The present study quantified the expression level of genes encoding components of the Hippo signaling pathway (LATS1, LATS2, YAP, and TAZ), AURKA and AURKB in CML patients at different stages of the disease, who were resistant or sensitive to imatinib mesylate therapy, and in healthy individuals. The expression levels of the target genes were correlated with the CML Sokal’s prognostic score. The most striking results were the LATS2 and AURKA overexpression in CML patients, the overexpression of TAZ and AURKB in CML patients at advanced phases and TAZ in CML IM-resistant. The development of drugs and/or identification of tumor markers for the Hippo signaling pathway and the Aurora kinase family, either alone or in combination, can optimize CML treatment by enhancing the susceptibility of leukemic cells to apoptosis and leading to a better disease prognosis.
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References
Melo JV, Barnes DJ. Chronic myeloid leukemia as a model of disease evolution in human cancer. Nat Rev Cancer. 2007;7(6):441–53.
Deininger MW, Vieira S, Mendiola R, et al. BCR–ABL1 tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res. 2000;60(7):2049–55.
Perrotti D, Neviani P. From mRNA metabolism to cancer therapy: chronic myelogenous leukemia shows the way. Clin Cancer Res. 2007;13(6):1638–42.
Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid leukaemia. Lancet. 2007;370(9584):342–50.
Goldman JM. Chronic myeloid leukemia: still a few questions. Exp Hematol. 2004;32(1):2–10.
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27(35):6041–51.
Sokal JE, Cox EB, Baccarani M, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood. 1984;63(4):789–99.
Ma Y, Yang Y, Wang F, et al. Hippo-YAP signaling pathway: a new paradigm for cancer therapy. Int J Cancer. 2015;137(10):2275–86.
Moroishi T, Hansen CG, Guan KL. The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer. 2015;15(2):73–9.
Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24(9):862–74. https://doi.org/10.1101/gad.1909210.
Xu T, Wang WS, Stewart RA, et al. Identifying tumor suppressors in genetic mosaics: the drosophila lats gene encodes a putative protein kinase. Development. 1995;121:1053–63.
Justice RW, Zilian O, Woods DF, et al. The drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 1995;9:534–46.
Tao W, Zhang S, Turenchalk GS, et al. Human homologue of the drosophila melanogaster lats tumor suppressor modulates CDC2 activity. Nat Genet. 1999;21:177–81.
Hori T, Takaori-Kondo A, Kamikubo Y, et al. Molecular cloning of a novel human protein kinase, kpm, that is homologous to warts/lats, a drosophila tumor suppressor. Oncogene. 2000;19:3101–9.
Yabuta N, Fujii T, Copeland NG, et al. Structure, expression and chromosome mapping of LATS2, a mammalian homologue of the drosophila tumor suppressor gene lats/warts. Genomics. 2000;63:263–70.
Edgar BA. From cell structure to transcription: Hippo forges a new path. Cell. 2006;124:267–73.
Pan D. Hippo signaling in organ size control. Genes Dev. 2007;21:886–97.
Overholtzer M, Zhang J, Smolen GA, et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci USA. 2006;103:12405–10.
Hao Y, Chun A, Cheung K, et al. Tumor suppressor LATS1 is a negative regulator of oncogene YAP. J Biol Chem. 2008;283:5496–509.
Lei QY, Zhang H, Zhao B, et al. TAZ promotes cell proliferation and epithelial mesenchymal transition and is inhibited by the hippo pathway. Mol Cell Biol. 2008;28:2426–36.
Chan H, Nousiainen M, Chalamalasetty RB, et al. The Ste20-like kinase Mst2 activates the human large tumor suppressor kinase Lats1. Oncogene. 2005;24:2076–86.
Praskova M, Xia F, Avruch J. MOBKL1A/MOBKL1B phosphorylation by MST1 and MST2 inhibits cell proliferation. Curr Biol. 2008;18:311–21.
Hergovich A, Schmitz D, Hemmings BA. The human tumour suppressor LATS1 is activated by human MOB1 at the membrane. Biochem Biophys Res Commun. 2006;345:50–8.
Cordenonsi M, Zanconato F, Azzolin L, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.
Bartucci M, Dattilo R, Moriconi C, et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2014;4(6):681–90.
Machado-Neto JA, de Melo Campos P, Olalla Saad ST, et al. YAP1 expression in myelodysplastic syndromes and acute leukemias. Leuk Lymphoma. 2014;55(10):2413–5.
Safari S, Movafagh A, Zare-Adollahi D, et al. MST1/2 and YAP1 gene expression in acute myeloid leukemia. Leuk Lymphoma. 2014;55(9):2189–91.
Yuen HF, McCrudden CM, Huang YH, et al. TAZ expression as a prognostic indicator in colorectal cancer. PLoS ONE. 2013;8:e54211. https://doi.org/10.1371/journal.pone.0054211
Farag SS. The potential role of aurora kinase inhibitors in haematological malignancies. Br J Haematol. 2011;5(5):561–79.
Yabuta N, Mukai S, Okada N, et al. The tumor suppressor Lats2 is pivotal in Aurora A and Aurora B signaling during mitosis. Cell Cycle. 2011;10(16):2724–36.
Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumors of haematopoietic and lymphoid tissues. 4th ed. Lyon: World Health Organization (WHO)/IARC; 2008.
Bartucci M, Dattilo R, Moriconi C, et al. TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene. 2015;34(6):681–90.
Wang L, Shi S, Guo Z, et al. Overexpression of YAP and TAZ is an independent predictor of prognosis in colorectal cancer and related to the proliferation and metastasis of colon cancer cells. PLoS ONE. 2013;8(6):e65539.
Boehrer S, Adès L, Tajeddine N, et al. Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome. Oncogene. 2009;28:2205–18.
Walters DK, Wu X, Tschumper RC, et al. Evidence for ongoing DNA damage in multiple myeloma cells as revealed by constitutive phosphorylation of H2AX. Leukemia. 2011;25:1344–53.
Cottini F, Hideshima T, Xu C, et al. Rescue of Hippo coactivator YAP1 triggers DNA damage-induced apoptosis in hematological cancers. Nat Med. 2014;20:599–606.
Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30:1–17.
Reuven N, Adler J, Meltser V, et al. The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl. Cell Death Differ. 2013;20:1330–40.
Sasi, et al. DDK promotes tumor chemoresistance and survival via multiple pathways. Neoplasia. 2017;19:439–50.
Ferreira AF, de Oliveira GL, Tognon R, et al. Apoptosis-related gene expression profile in chronic myeloid leukemia patients after imatinib mesylate and dasatinib therapy. Acta Haematol. 2015;133(4):354–64.
Nakai H, Misawa S, Toguchida J, et al. Frequent p53 gene mutations in blast crisis of chronic myelogenous leukemia, especially in myeloid crisis harboring loss of chromosome 17p. Cancer Res. 1992;52:6588–93.
Tian T, Li A, Lu H, et al. TAZ promotes temozolomide resistance by upregulating MCL-1 in human glioma cells. Biochem Biophys Res Commun. 2015;463(4):638–43.
Andrews PD, Knatko E, Moore WJ, et al. Mitotic mechanics: the Auroras come into view. Curr Opin Cell Biol. 2003;15(6):672–83.
Farag SS. The potential role of aurora kinase inhibitors in haematological malignancies. Br J Haematol. 2011;155(5):561–79.
Ikezoe T, Takeuchi T, Yang J, et al. Analysis of Aurora B kinase in non-Hodgkin lymphoma. Lab Invest. 2009;89:1364–73.
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This work was supported by Coordination for the Improvement of Higher Education Personnel (CAPES) and FAPESP (2015-23555-3 and 2015-21237-4).
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All procedures performed in studies involving human participants complied with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.
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Marsola, A.P.Z.C., Simões, B.P., Palma, L.C. et al. Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia. Med Oncol 35, 26 (2018). https://doi.org/10.1007/s12032-018-1079-6
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DOI: https://doi.org/10.1007/s12032-018-1079-6