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Therapy-Induced Changes in the Gene Expression Profile of Patients with Hematological Diseases

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Therapy-Induced Changes in the Gene Expression Profile of Patients with Hematological Diseases Department of MEDICINE, HEMATOLOGY CANCER RESEARCH CENTER-IBMCC (USAL-CSIC) Doctoral Dissertation Therapy-induced changes in the gene expression profile of patients with hematological diseases With the approval of Salamanca University, Department of Medicine, this thesis will be defended on 2th September 2019 Supervisors: Prof. Dr. Jesús María Hernández Rivas Dra. M del Rocío Benito Sánchez Dra. Ana E. Rodríguez Vicente Jesús María Hernández Sánchez, Salamanca, 2019 D. Jesús María Hernández Rivas, Doctor en Medicina, Catedrático del Departamento de Medicina de la Universidad de Salamanca, Médico Adjunto del Servicio de Hematología del Hospital Clínico Universitario de Salamanca e Investigador del Centro de Investigación del Cáncer de Salamanca, D.a María del Rocío Benito Sánchez, Doctora en Ciencias Biológicas e Investigadora del Centro de Investigación del Cáncer de Salamanca, D.a Ana Eugenia Rodríguez Vicente, Doctora por la universidad de Salamanca e Investigadora del Centro de Investigación del Cáncer de Salamanca, CERTIFICAN Que D. Jesús María Hernández Sánchez graduado en Farmacia por la Universidad de Salamanca, ha realizado bajo nuestra dirección el trabajo de Tesis Doctoral titulado “Therapy-induced changes in the gene expression profile of patients with hematological diseases”, y que éste reúne, a nuestro juicio, las condiciones de originalidad y calidad científica requeridas para su presentación y defensa ante el tribunal correspondiente para optar al grado de Doctor, con mención “Doctor International”, por la Universidad de Salamanca. Y para que así conste a los efectos oportunos, firmamos el presente certificado en Salamanca, a 2 de Julio de 2019. Fdo: Prof. Dr. Jesús M. Hernández Rivas Dra. M. del Rocío Benito Sánchez Dra. Ana Eugenia Rodríguez Vicente This thesis was performed being Jesús María Hernández Sánchez partially supported by “Beca de investigación de la fundación española de hematología y hemoterapia” Acknowledgments: • PI17/01741: Caracterización de los SMD de bajo riesgo sin sideroblastos en anillo: de las CPH a las vesículas extracelulares circulantes. 2018-2021 • GRS 1873/A/18: Ultrasecuenciación del ARN (RNA-seq) en pacientes con trombocitopenia inmune tratados con eltrombopag. Búsqueda de biomarcadores de respuesta y de nuevos mecanismos de acción de eltrombopag. 2018-2019 • GRS 1349/A/16: Impacto clínico y pronóstico de la presencia de mutaciones somáticas en pacientes con SMD de bajo riesgo sin sideroblastos en anillo. 2016- 2017 • Celgene Corporation, Spain. Determinación de la alteración 5q- en pacientes diagnosticados de SMD. 2013 • Novartis Farmacéutica, Spain: Estudio observacional y prospectivo sobre la influencia del tratamiento inhibidor selectivo de JAK 1/2 en el perfil de expresión génica de pacientes con mielofibrosis. 2015 • Roche IVS: IRON-III (Interlaboratory robustness of Next generation Sequencing). 2014-2015 Scientific contribution during the thesis performed by Jesús María Hernández Sánchez: Published papers [1] M. Hernández-Sánchez, A.E. Rodríguez-Vicente, I. González-Gascón y Marín, M. Quijada- Álamo, J.M. Hernández-Sánchez, M. Martín-Izquierdo, J.Á. Hernández-Rivas, R. Benito, J.M. Hernández-Rivas, DNA damage response-related alterations define the genetic background of patients with chronic lymphocytic leukemia and chromosomal gains, Experimental Hematology. 72 (2019) 9–13. doi:10.1016/j.exphem.2019.02.003. [2] J.M. Bastida, O. López-Godino, A. Vicente-Sánchez, S. Bonanad-Boix, B. Xicoy-Cirici, J.M. Hernández-Sánchez, E. Such, J. Cervera, J.C. Caballero-Berrocal, F. López-Cadenas, M. Arnao-Herráiz, I. Rodríguez, I. Llopis-Calatayud, M.J. Jiménez, M.C. del Cañizo-Roldán, M. Díez-Campelo, Hidden myelodysplastic syndrome (MDS): A prospective study to confirm or exclude MDS in patients with anemia of uncertain etiology, International Journal of Laboratory Hematology. 41 (2019) 109–117. doi:10.1111/ijlh.12933. [3] J.M. Bastida, R. Benito, M.L. Lozano, A. Marín-Quilez, K. Janusz, M. Martín-Izquierdo, J. Hernández-Sánchez, V. Palma-Barqueros, J.M. Hernández-Rivas, J. Rivera, J.R. González- Porras, Molecular Diagnosis of Inherited Coagulation and Bleeding Disorders, Semin Thromb Hemost. (2019) s-0039-1687889. doi:10.1055/s-0039-1687889. [4] I. García-Tuñón, V. Alonso-Pérez, E. Vuelta, S. Pérez- Ramos, M. Herrero, L. Méndez, J.M. Hernández-Sánchez, M. Martín-Izquierdo, R. Saldaña, J. Sevilla, F. Sánchez- Guijo, J.M. Hernández-Rivas, M. Sánchez-Martín, Splice donor site sgRNAs enhance CRISPR/Cas9- mediated knockout efficiency, PLoS ONE. 14 (2019) e0216674. doi:10.1371/journal.pone.0216674. [5] J.M. Bastida, M.L. Lozano, R. Benito, K. Janusz, V. Palma-Barqueros, M. Del Rey, J.M. Hernández-Sánchez, S. Riesco, N. Bermejo, H. González-García, A. Rodriguez-Alén, C. Aguilar, T. Sevivas, M.F. López-Fernández, A.E. Marneth, B.A. van der Reijden, N.V. Morgan, S.P. Watson, V. Vicente, J.M. Hernández-Rivas, J. Rivera, J.R. González-Porras, Introducing high-throughput sequencing into mainstream genetic diagnosis practice in inherited platelet disorders, Haematologica. 103 (2018) 148–162. doi:10.3324/haematol.2017.171132. [6] J. Sanchez-Garcia, J. Falantes, A. Medina Perez, F. Hernandez-Mohedo, L. Hermosin, A. Torres-Sabariego, A. Bailen, J.M. Hernandez-Sanchez, M. Solé Rodriguez, F.J. Casaño, C. Calderon, M. Labrador, M. Vahí, J. Serrano, E. Lumbreras, J.M. Hernández-Rivas, On behalf of Grupo Andaluz SMD, Prospective randomized trial of 5 days azacitidine versus supportive care in patients with lower-risk myelodysplastic syndromes without 5q deletion and transfusion-dependent anemia, Leukemia & Lymphoma. 59 (2018) 1095–1104. doi:10.1080/10428194.2017.1366998. [7] J.M. Bastida, R. Benito, K. Janusz, M. Díez-Campelo, J.M. Hernández-Sánchez, S. Marcellini, M. Girós, J. Rivera, M.L. Lozano, A. Hortal, J.M. Hernández-Rivas, J.R. González-Porras, Two novel variants of the ABCG5 gene cause xanthelasmas and macrothrombocytopenia: a brief review of hematologic abnormalities of sitosterolemia, Journal of Thrombosis and Haemostasis. 15 (2017) 1859–1866. doi:10.1111/jth.13777. [8] M. Forero-Castro, C. Robledo, R. Benito, I. Bodega-Mayor, I. Rapado, M. Hernández- Sánchez, M. Abáigar, J. Maria Hernández-Sánchez, M. Quijada-Álamo, J. María Sánchez- Pina, M. Sala-Valdés, F. Araujo-Silva, A. Kohlmann, J. Luis Fuster, M. Arefi, N. de las Heras, S. Riesco, J.N. Rodríguez, L. Hermosín, J. Ribera, M. Camos Guijosa, M. Ramírez, C.D. de Heredia Rubio, E. Barragán, J. Martínez, J.M. Ribera, E. Fernández-Ruiz, J.-M. Hernández- Rivas, Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia, British Journal of Cancer. 117 (2017) 256–265. doi:10.1038/bjc.2017.152. [9] M. Quijada-Álamo, M. Hernández-Sánchez, C. Robledo, J.-M. Hernández-Sánchez, R. Benito, A. Montaño, A.E. Rodríguez-Vicente, D. Quwaider, A.-Á. Martín, M. García-Álvarez, M.J. Vidal-Manceñido, G. Ferrer-Garrido, M.-P. Delgado-Beltrán, J. Galende, J.-N. Rodríguez, G. Martín-Núñez, J.-M. Alonso, A. García de Coca, J.A. Queizán, M. Sierra, C. Aguilar, A. Kohlmann, J.-Á. Hernández, M. González, J.-M. Hernández-Rivas, Next-generation sequencing and FISH studies reveal the appearance of gene mutations and chromosomal abnormalities in hematopoietic progenitors in chronic lymphocytic leukemia, Journal of Hematology & Oncology. 10 (2017) 83. doi:10.1186/s13045-017-0450-y. [10] A.M. Dubuc, M.S. Davids, M. Pulluqi, O. Pulluqi, K. Hoang, J.M. Hernandez-Sánchez, C. Schlich, J.M. Hernández-Rivas, J.R. Brown, P. Dal Cin, FISHing in the dark: How the combination of FISH and conventional karyotyping improves the diagnostic yield in CpG- stimulated chronic lymphocytic leukemia: Combined FISH and Karyotyping Improves Diagnostic Yield in CLL, American Journal of Hematology. 91 (2016) 978–983. doi:10.1002/ajh.24452. [11] A.E. Rodríguez-Vicente, E. Lumbreras, J.M. Hernández, M. Martín, A. Calles, C.L. Otín, S.M. Algarra, D. Páez, M. Taron, Pharmacogenetics and pharmacogenomics as tools in cancer therapy, Drug Metabolism and Personalized Therapy. 31 (2016). doi:10.1515/dmpt-2015- 0042. [12] M. Forero-Castro, C. Robledo, E. Lumbreras, R. Benito, J.M. Hernández-Sánchez, M. Hernández-Sánchez, J.L. García, L.A. Corchete-Sánchez, M. Tormo, P. Barba, J. Menárguez, J. Ribera, C. Grande, L. Escoda, C. Olivier, E. Carrillo, A. García de Coca, J.-M. Ribera, J.M. Hernández-Rivas, The presence of genomic imbalances is associated with poor outcome in patients with burkitt lymphoma treated with dose-intensive chemotherapy including rituximab, British Journal of Haematology. 172 (2016) 428–438. doi:10.1111/bjh.13849. [13] M.A. Dasi, R. Gonzalez-Conejero, S. Izquierdo, J. Padilla, J.L. Garcia, N. Garcia-Barberá, B. Argilés, M.E. de la Morena-Barrio, J.M. Hernández-Sánchez, J.M. Hernández-Rivas, V. Vicente, J. Corral, Uniparental disomy causes deficiencies of vitamin K-dependent proteins, Journal of Thrombosis and Haemostasis. 14 (2016) 2410–2418. doi:10.1111/jth.13517. [14] J.C. Caballero Berrocal, Mercedes Sánchez Barba, Jesús M. Hernández Sánchez, Monica del Rey, Kamila Janusz, C. Chillón, Esperanza Such, Guillermo F Sanz, Ana María Hurtado López, C. Calderón Cabrera, David Valcarcel, Eva Lumbreras, Cristina Robledo, María Abáigar, F. López Cadenas, M. Cabrero, A. Redondo-Guijo, J.M. Hernández Rivas, Maria-Consuelo del Cañizo, M. Díez Campelo, Chronic Graft Versus Host Disease could ameliorate the impact of adverse somatic mutations in patients with Myelodysplastic Syndromes and Hematopoietic Stem Cell Transplantation. Annals of
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