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Hippo pathway-related genes expression is deregulated in myeloproliferative neoplasms

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Abstract

Myeloproliferative neoplasms (MPN) are hematological disorders characterized by increased proliferation of precursor and mature myeloid cells. MPN patients may present driver mutations in JAK2, MPL, and CALR genes, which are essential to describe the molecular mechanisms of MPN pathogenesis. Despite all the new knowledge on MPN pathogenesis, many questions remain to be answered to develop effective therapies to cure MPN or impair its progression to acute myeloid leukemia. The present study examined the expression levels of the Hippo signaling pathway members in patients with polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), as well as the role that they play in disease pathogenesis. The Hippo pathway is a tumor suppressor pathway that participates in the regulation of cell proliferation, differentiation, and death. Our main finding was that the expression of tumor suppressor genes from Hippo pathway were downregulated and seemed to be associated with cell resistance to apoptosis and increased proliferation rate. Therefore, the decreased expression of Hippo pathway-related genes may contribute to the malignant phenotype, apoptosis resistance, and cell proliferation in MPN pathogenesis.

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References

  1. Dameshek W. Some speculations on the myeloproliferative syndromes. Blood. 1951;6:372–5.

    Article  CAS  PubMed  Google Scholar 

  2. Mesa RA, Verstovsek S, Cervantes F, Barosi G, Reilly JT, Dupriez B, et al. Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post-PV MF), post essential thrombocythemia myelofibrosis (post-ET MF), blast phase PMF (PMF-BP): Consensus on terminology by the international working group for myelofibrosis research and treatment (IWG-MRT). Leuk Res. 2007;31:737–40.

    Article  PubMed  Google Scholar 

  3. C. Diaconu C, Gurban P, Mambet C, Chivu-Economescu M, G. Necula L, Matei L, et al. Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms. In: Gali-Muhtasib H, Nasser Rahal O, editors. Programmed Cell Death. IntechOpen; 2020 [cited 2021 Mar 23]. Available from: https://www.intechopen.com/books/programmed-cell-death/programmed-cell-death-deregulation-in-bcr-abl1-negative-myeloproliferative-neoplasms

  4. Tognon R, Gasparotto EP, Neves RP, Nunes NS, Ferreira AF, Palma PV, et al. Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis. J Hematol Oncol. 2012;5:2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. James C, Ugo V, Le Couédic J-P, Staerk J, Delhommeau F, Lacout C, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. 2005;434:1144–8.

    Article  CAS  PubMed  Google Scholar 

  6. Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJP, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7:387–97.

    Article  CAS  PubMed  Google Scholar 

  7. Huijsmans CJJ, Poodt J, Savelkoul PHM, Hermans MHA. Sensitive detection and quantification of the JAK2V617F allele by real-time PCR. J Mol Diagn. 2011;13:558–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kodama T, Hikita H, Kawaguchi T, Shigekawa M, Shimizu S, Hayashi Y, et al. Mcl-1 and Bcl-xL regulate Bak/Bax-dependent apoptosis of the megakaryocytic lineage at multistages. Cell Death Differ. 2012;19:1856–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M, et al. MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood. 2006;108:3472–6.

    Article  CAS  PubMed  Google Scholar 

  10. Plo I, Bellanné-Chantelot C, Mosca M, Mazzi S, Marty C, Vainchenker W. Genetic alterations of the thrombopoietin/MPL/JAK2 axis impacting megakaryopoiesis. Front Endocrinol (Lausanne). 2017;8:234.

    Article  Google Scholar 

  11. Chaligné R, Tonetti C, Besancenot R, Roy L, Marty C, Mossuz P, et al. New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia. 2008;22:1557–66.

    Article  PubMed  CAS  Google Scholar 

  12. Araki M, Komatsu N. Novel molecular mechanism of cellular transformation by a mutant molecular chaperone in myeloproliferative neoplasms. Cancer Sci. 2017;108:1907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chachoua I, Pecquet C, El-Khoury M, Nivarthi H, Albu R-I, Marty C, et al. Thrombopoietin receptor activation by myeloproliferative neoplasm associated calreticulin mutants. Blood. 2016;127:1325–35.

    Article  CAS  PubMed  Google Scholar 

  14. Salati S, Genovese E, Carretta C, Zini R, Bartalucci N, Prudente Z, et al. Calreticulin Ins5 and Del52 mutations impair unfolded protein and oxidative stress responses in K562 cells expressing CALR mutants. Sci Rep. 2019;9:10558.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003;114:445–56.

    Article  CAS  PubMed  Google Scholar 

  16. Couzens AL, Knight JDR, Kean MJ, Teo G, Weiss A, Dunham WH, et al. Protein interaction network of the mammalian Hippo pathway reveals mechanisms of kinase-phosphatase interactions. Sci Signal. 2013;6:rs15.

    Article  PubMed  CAS  Google Scholar 

  17. Hong W, Guan K-L. The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway. Semin Cell Dev Biol. 2012;23:785–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22:1962–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Barbui T, Thiele J, Gisslinger H, Kvasnicka HM, Vannucchi AM, Guglielmelli P, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8:15.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dijkstra-Tiekstra MJ, Setroikromo AC, Kraan M, Gkoumassi E, de Wildt-Eggen J. Is hydroxyethyl starch necessary for sedimentation of bone marrow? Transfus Apheres Sci. 2015;52:94–8.

    Article  Google Scholar 

  21. Chicaybam L, Barcelos C, Peixoto B, Carneiro M, Limia CG, Redondo P, et al. An efficient electroporation protocol for the genetic modification of mammalian cells. Front Bioeng Biotechnol. 2017. https://doi.org/10.3389/fbioe.2016.00099/full.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Guo H, Hao R, Wei Y, Sun D, Sun S, Zhang Z. Optimization of electrotransfection conditions of mammalian cells with different biological features. J Membr Biol. 2012;245:789–95.

    Article  CAS  PubMed  Google Scholar 

  23. Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development. 2011;138:9–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Badouel C, Garg A, McNeill H. Herding Hippos: regulating growth in flies and man. Curr Opin Cell Biol. 2009;21:837–43.

    Article  CAS  PubMed  Google Scholar 

  25. Kosaka Y, Mimori K, Tanaka F, Inoue H, Watanabe M, Mori M. Clinical significance of the loss of MATS1 mRNA expression in colorectal cancer. Int J Oncol. 2007;31:333–8.

    CAS  PubMed  Google Scholar 

  26. Sasaki H, Kawano O, Endo K, Suzuki E, Yukiue H, Kobayashi Y, et al. Human MOB1 expression in non-small-cell lung cancer. Clin Lung Cancer. 2007;8:273–6.

    Article  CAS  PubMed  Google Scholar 

  27. Ji T, Liu D, Shao W, Yang W, Wu H, Bian X. Decreased expression of LATS1 is correlated with the progression and prognosis of glioma. J Exp Clin Cancer Res. 2012;31:67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. de Cristofaro T, Di Palma T, Ferraro A, Corrado A, Lucci V, Franco R, et al. TAZ/WWTR1 is overexpressed in papillary thyroid carcinoma. Eur J Cancer. 2011;47:926–33.

    Article  PubMed  CAS  Google Scholar 

  29. Dhyani A, Duarte ASS, Machado-Neto JA, Favaro P, Ortega MM, Olalla Saad ST. ANKHD1 regulates cell cycle progression and proliferation in multiple myeloma cells. FEBS Lett. 2012;586:4311–8.

    Article  CAS  PubMed  Google Scholar 

  30. Hartmann EM, Campo E, Wright G, Lenz G, Salaverria I, Jares P, et al. Pathway discovery in mantle cell lymphoma by integrated analysis of high-resolution gene expression and copy number profiling. Blood. 2010;116:953–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Machado-Neto JA, de Melo CP, Olalla Saad ST, Traina F. YAP1 expression in myelodysplastic syndromes and acute leukemias. Leuk Lymphoma. 2014;55:2413–5.

    Article  PubMed  Google Scholar 

  32. Gholami M, Mirfakhraie R, Movafagh A, Jalaeekhoo H, Kalahroodi R, Zare-Abdollahi D, et al. The expression analysis of LATS2 gene in de novo AML patients. Med Oncol. 2014;31:961.

    Article  PubMed  CAS  Google Scholar 

  33. Cottini F, Hideshima T, Xu C, Sattler M, Dori M, Agnelli L, et al. Rescue of Hippo coactivator YAP1 triggers DNA damage–induced apoptosis in hematological cancers. Nat Med. 2014;20:599–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jansson L, Larsson J. Normal hematopoietic stem cell function in mice with enforced expression of the hippo signaling effector YAP1. PLoS ONE. 2012;7:e32013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nehme NT, Schmid JP, Debeurme F, André-Schmutz I, Lim A, Nitschke P, et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood. 2012;119:3458–68.

    Article  CAS  PubMed  Google Scholar 

  36. Abdollahpour H, Appaswamy G, Kotlarz D, Diestelhorst J, Beier R, Schäffer AA, et al. The phenotype of human STK4 deficiency. Blood. 2012;119:3450–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kawahara M, Hori T, Chonabayashi K, Oka T, Sudol M, Uchiyama T. Kpm/Lats2 is linked to chemosensitivity of leukemic cells through the stabilization of p73. Blood. 2008;112:3856–66.

    Article  CAS  PubMed  Google Scholar 

  38. Ogawa S, Yokoyama Y, Suzukawa K, Nanmoku T, Kurita N, Seki M, et al. Identification of a fusion gene composed of a Hippo pathway gene MST2 and a common translocation partner ETV6 in a recurrent translocation t(8;12)(q22;p13) in acute myeloid leukemia. Ann Hematol. 2015;94:1431–3.

    Article  PubMed  Google Scholar 

  39. Stoner SA, Yan M, Liu KTH, Arimoto K-I, Shima T, Wang H-Y, et al. Hippo kinase loss contributes to del(20q) hematologic malignancies through chronic innate immune activation. Blood. 2019;134:1730–44.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Sun S, Ravid K. Role of a serine/threonine kinase, Mst1, in megakaryocyte differentiation. J Cell Biochem. 2000;76:44–60.

    Article  CAS  Google Scholar 

  41. Sakhinia E, Farahangpour M, Tholouli E, Liu Yin JA, Hoyland JA, Byers RJ. Comparison of gene-expression profiles in parallel bone marrow and peripheral blood samples in acute myeloid leukaemia by real-time polymerase chain reaction. J Clin Pathol. 2006;59:1059–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wiestner A, Marti GE, Billings EM, Liu H, Lee E, White T, et al. Differential gene expression in CLL cells from bone marrow and peripheral blood suggests a role of bone marrow stroma in leukemic cell proliferation. Blood. 2005;106:708–708.

    Article  Google Scholar 

  43. Furth N, Aylon Y. The LATS1 and LATS2 tumor suppressors: beyond the Hippo pathway. Cell Death Differ. 2017;24:1488–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ke H, Pei J, Ni Z, Xia H, Qi H, Woods T, et al. Putative tumor suppressor Lats2 induces apoptosis through downregulation of Bcl-2 and Bcl-xL. Exp Cell Res. 2004;298:329–38.

    Article  CAS  PubMed  Google Scholar 

  45. Guo C, Liang C, Yang J, Hu H, Fan B, Liu X. LATS2 inhibits cell proliferation and metastasis through the Hippo signaling pathway in glioma. Oncol Rep. 2019. https://doi.org/10.3892/or.2019.7065.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Du L. Jak/Stat and Hippo Signaling Pathways Independently Regulate the Same Target Genes To Control Cell Proliferation [Internet]. Digital Repository at the University of Maryland; 2014 [cited 2021 Mar 26]. Available from: http://hdl.handle.net/1903/16257

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Funding

This study was supported by the Coordination for the Improvement of Higher Education Personnel (CAPES; Finance Code 001); the São Paulo Research Foundation (FAPESP; Regular Research Grant #2018/19714-7; CTC Grant #2013/08135-2; INCTC Grant #2014/50947-7; Young Investigator Grant# 2015/21866-1), and by the National Council for Scientific and Technological Development (CNPq Grants #163064/2018-0, #169093/2018-2, and #305959/2018-2). MCC and MGBC are recipients from FAPESP scholarships (Grants #2014/04234-9 and #2015/23555-3, respectively).

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Authors and Affiliations

  1. Laboratório de Fisiopatologia das Doenças Hematológicas, Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo – USP, Av. do Café, s/nº. Campus Universitário, Ribeirão Preto, SP, 14040-903, Brazil

    Maira da Costa Cacemiro, Juçara Gastaldi Cominal, Luiz Miguel Pereira, Maria Gabriela Berzoti-Coelho, Giovana Michelassi Berbel, Luciana Baroni, Tathiane Malta, Natalia de Souza Nunes, Ana Patricia Yatsuda & Fabíola Attié de Castro

  2. Department of Pharmacy, Federal University of Juiz de Fora, Campus Governador Valadares, Governador Valadares, MG, Brazil

    Raquel Tognon

  3. Medical Imaging, Hematology and Oncology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil

    Lorena Lobo de Figueiredo-Pontes

  4. Euryclides de Jesus Zerbini Transplant Hospital, São Paulo, SP, Brazil

    Elizabeth Xisto Souto

Authors
  1. Maira da Costa Cacemiro
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  2. Juçara Gastaldi Cominal
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  3. Luiz Miguel Pereira
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by MdCC, JGC, LMP, MGB-C, GMB, LB, TM, RT, NdSN, and EXS. The first draft of the manuscript was written by MdCC and FAdC. The manuscript was reviewed by LLdF-P, APY, and FAdC. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Maira da Costa Cacemiro or Fabíola Attié de Castro.

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Cacemiro, M.C., Cominal, J.G., Pereira, L.M. et al. Hippo pathway-related genes expression is deregulated in myeloproliferative neoplasms. Med Oncol 39, 97 (2022). https://doi.org/10.1007/s12032-022-01696-x

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