Cabecera lazomsalas2019 11 08 CBMSO CSIC UAM

Wednesday, 20th November 2019

Development of the human lymphohematopoietic system

toribio grupo400



María Luisa Toribio García







Research summary:

     Our group is interested in understanding the mechanisms determining human hematopoietic stem and progenitor cell commitment to the T-cell lineage. In the last years, our research has focussed on the identification of cellular and molecular players involved in the generation of functional T cells in the human thymus with two main goals: 1) deciphering the particular changes of the T-cell developmental program undertaken by thymus-seeding progenitors that lead to the generation of T-cell acute lymphoblastic leukemia (T-ALL) and 2) characterizing the alterations of the thymic microenvironment that parallel age-related thymic involution, iatrogenic effects, and/or thymic aplasia, which must be the focus of novel regenerative approaches. The ultimate goal is identifying key molecular targets for developing specific therapeutic strategies, and to provide proof of concept of their suitability in preclinical models for later translation to the clinic.



Figure-1: Expression of DLL1 Notch ligand in human tonsil. DLL1: Delta-like ligand 1. GC: Germinal Centre.


     Our loss- and gain-of-function genetic approaches, in vitro cell differentiation assays and humanized mouse models of disease, have highlighted the prevalent role that Notch1 signaling plays as a key pathway involved in both physiological and pathological human T cell development, and also as a crucial regulator of thymic epithelial cell homeostasis and ageing. We found that spatiotemporal regulation of Notch1 signaling guides the formation of particular thymus niches that support the specification of distinct hematopopietic cell types, and also controls the age-associated functional decline of the thymus microenvironment and, thus, the emergence of immunosenescence. Collectively, we have provided critical information of key Notch1 targets specifically involved in: 1) expansion of normal and pathological pre-T cells, 2) interactions between pre-leukemic T-ALL cells and the bone marrow microenvironment, which are mandatory for leukemia-initiating cell generation and progression, and 3) age-associated involution of the human thymus. Therefore, our data highlight the relevance of Notch target manipulation as a promising therapeutic strategy for both T-ALL and immunosenescent patients.



Figure-2: Analysis of in vivo tumor progression of luciferase-expressing human primary T-ALL cells upon xenotrasplantation into immunodeficient mice.




Last publications (click on the name of the journal to open the article):

López-Guerra M, Xargay-Torrent S, Fuentes P, Roldán J, González-Farré B, Rosich L, Silkenstedt E, García-León MJ, Lee-Vergés E, Giménez N, Giró A, Aymerich M, Villamor N, Delgado J, López-Guillermo A, Puente XS, Campo E, Toribio ML, Colomer D. Specific NOTCH1 antibody targets DLL4-induced proliferation, migration, and angiogenesis in NOTCH1-mutated CLL cells. Oncogene 2019 Oct 15.

- González-García S, Mosquera M, Fuentes P, Palumbo T, Escudero A, Pérez-Martínez A, Ramírez-Orellana M, Corcoran AE, Toribio ML. IL-7R is essential for leukemia-initiating cell activity and pathogenesis of T-cell acute lymphoblastic leukemia. Blood 2019 Sep 17.

- Sánchez-Martínez D, Baroni ML, Gutierrez-Agüera F, Roca-Ho H, Blanch-Lombarte O, González-García S, Torrabadell M, Junca J, Ramírez-Orellana M, Velasco-Hernández T, Bueno C, Fuster JL, Prado JG, Calvo J, Uzan B, Cools J, Camos M, Pflumio F, Toribio ML, Menéndez P. Fratricide-resistant CD1a-specific CAR T-cells for the treatment of cortical T-cell acute lymphoblastic leukemia. Blood 2019;133(21):2291-2304.

- García-León MJ, Fuentes P, de la Pompa JL and Toribio ML. Dynamic regulation of Notch1 activation and Notch ligand expression in human thymus developmentDevelopment 2018;145(16).

- García-Peydró M, Fuentes P, Mosquera M. García-León MJ, Alcain J, Rodríguez A, García de Miguel P, Menéndez P, Weijer K, Spits H, Scadden DT, Cuesta-Mateos C, Muñoz-Calleja C, Sánchez-Madrid F and Toribio ML. The NOTCH1-CD44 axis drives pathogenesis in a T-cell acute lymphoblastic leukemia model. The Journal of Clinical Investigation 2018;128(7):2802-2818.

- Robles-Valero J, Lorenzo-Martín LF, Menacho-Márquez M, Fernández-Pisonero I, Abad A, Camós M, Toribio ML, Espinosa L, Bigas A, Bustelo XR. A Paradoxical Tumor-Suppressor Role for the Rac1 Exchange Factor Vav1 in T Cell Acute Lymphoblastic Leukemia. Cancer Cell 2017;32(5):608-623.

- Martín-Gayo E, González-García S, García-León MJ, Murcia-Ceballos A, Alcain J, García-Peydró M, Allende L, de Andrés B, Gaspar ML, Toribio ML. Spatially restricted JAG1-Notch signaling in human thymus provides suitable DC development niches. The Journal of Experimental Medicine 2017;214(11):3361-3379.

Botón web Science Editors Choice

- Sánchez-Díaz R, Blanco-Dominguez R, Lasarte S, Tsilingiri K, Martín-Gayo E, Linillos-Pradillo B, de la Fuente H, Sánchez-Madrid F, Nakagawa R, Toribio ML, Martín P.Thymus-derived Treg cell development is regulated by C-type-lectin-mediated BIC/miRNA155 expression. Molecular and Cellular Biology 2017;37(9).

Tremblay CS, Brown FC, Collett M, Saw J, Chiu SK, Sonderegger SE, Lucas SE, Alserihi R, Chau N, Toribio ML, McCormack MP, Chircop M, Robinson PJ, Jane SM, Curtis DJ. Loss-of-function mutations of Dynamin 2 promote T-ALL by enhancing IL-7 signalling. Leukemia 2016;30(10):1993-2001. 

Toribio MLModeling altered human T-cell development. Blood 2016;128(6):743-5.

Ogando J, Tardáguila M, Díaz-Alderete A, Usategui A, Miranda-Ramos V, Martínez-Herrera DJ, de la Fuente L, García-León MJ, Moreno MC, Escudero S, Cañete JD, Toribio ML, Cases I, Pascual-Montano A, Pablos JL, Mañes S. Notch-regulated miR-223 targets the aryl hydrocarbon receptor pathway and increases cytokine production in macrophages from rheumatoid arthritis patients. Scientific Reports 2016;6:20223.

- Ayllon V, Bueno C, Ramos-Mejía V, Navarro-Montero O, Prieto C, Real PJ, Romero T, García-León MJ,Toribio ML, Bigas A, Menendez P. The Notch ligand DLL4 specifically marks human hematoendothelial progenitors and regulates their hematopoietic fateLeukemia 2015;29(8):1741-53.

Rodríguez-Fraticelli AE, Bagwell J, Bosch-Fortea M, Boncompain G, Reglero-Real N, García-León MJ, Andrés G, Toribio ML, Alonso MA, Millán J, Perez F, Bagnat M, Martín-Belmonte F. Developmental regulation of apical endocytosis controls epithelial patterning in vertebrate tubular organs. Nature Cell Biology 2015;17(3):241-50.

Garcillán B, Marin AV, Jiménez-Reinoso A, Briones AC, Muñoz-Ruiz M, García-León MJ, Gil J, Allende LM, Martínez-Naves E, Toribio ML, Regueiro JR. γδ T Lymphocytes in the Diagnosis of Human T Cell Receptor Immunodeficiencies. Frontiers in Immunology 2015;6:20.

Rodriguez RM, Suarez-Alvarez B, Mosén-Ansorena D, García-Peydró M, Fuentes P, García-León MJ, Gonzalez-Lahera A, Macias-Camara N, Toribio ML, Aransay AM, Lopez-Larrea C. Regulation of the transcriptional program by DNA methylation during human αβ T-cell developmentNucleic Acids Research 2015;43(2):760-74.

- Cortés JR, Sánchez-Díaz R, Bovolenta ER, Barreiro O, Lasarte S, Matesanz-Marín A, Toribio ML, Sánchez-Madrid F, Martín P. Maintenance of immune tolerance by Foxp3(+) regulatory T cells requires CD69 expressionJournal of Autoimmunity 2014;55:51-62.

- Domínguez-Soto A, de las Casas-Engel M, Bragado R, Medina-Echeverz J, Aragoneses-Fenoll L, Martín-Gayo E, van Rooijen N, Berraondo P, Toribio ML, Moro MA, Cuartero I, Castrillo A, Sancho D, Sánchez-Torres C, Bruhns P, Sánchez-Ramón S, Corbí AL. Intravenous immunoglobulin promotes antitumor responses by modulating macrophage polarizationJournal of Immunology 2014;193(10):5181-9.

- Galetto R, Lebuhotel C, Poirot L, Gouble A, Toribio ML, Smith J, Scharenberg APre-TCRalpha supports CD3-dependent reactivation and expansion of TCRalpha-deficient primary human T-cellsMolecular Theraphy - Methods & Clinical Development 2014;1:14021.

- Rubio R, Gutierrez-Aranda I, Sáez-Castillo AI, Labarga A, Rosu-Myles M, Gonzalez-Garcia S, Toribio ML, Menendez P, Rodriguez R. The differentiation stage of p53-Rb-deficient bone marrow mesenchymal stem cells imposes the phenotype of in vivo sarcoma developmentOncogene 2013;32(41):4970-80.

- González-García S, García-Peydró M, Alcain J, Toribio ML. Notch1 and IL-7 receptor signalling in early T-cell development and leukaemiaCurrent Topics in Microbiology and Immunology 2012;360:47-73.

- Zenatti PP, Ribeiro D, Li W, Zuurbier L, Silva MC, Paganin M, Tritapoe J, Hixon JA, Silveira AB, Cardoso BA, Sarmento LM, Correia N, Toribio ML, Kobarg J, Horstmann M, Pieters R, Brandalise SR, Ferrando AA, Meijerink JP, Durum SK, Yunes JA, Barata JT. Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemiaNature Genetics 2011;43(10):932-9.

- Esteve P, Sandonìs A, Cardozo M, Malapeira J, Ibañez C, Crespo I, Marcos S, Gonzalez-Garcia S, Toribio ML, Arribas J, Shimono A, Guerrero I, Bovolenta P. SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesisNature Neuroscience 2011;14(5):562-9.

- Puig-Kröger A, Aguilera-Montilla N, Martínez-Nuñez R, Domínguez-Soto A, Sánchez-Cabo F, Martín-Gayo E, Zaballos A, Toribio ML, Groner Y, Ito Y, Dopazo A, Corcuera MT, Alonso Martín MJ, Vega MA, Corbí AL. The novel RUNX3/p33 isoform is induced upon monocyte-derived dendritic cell maturation and downregulates IL-8 expressionImmunobiology 2010;215(9-10):812-20.

- Martín-Gayo E, Sierra-Filardi E, Corbí AL, Toribio ML. Plasmacytoid dendritic cells resident in human thymus drive natural Treg cell developmentBlood 2010;115(26):5366-75.

- Van Vlierberghe P, Palomero T, Khiabanian H, Van der Meulen J, Castillo M, Van Roy N, De Moerloose B, Philippé J, González-García S, Toribio ML, Taghon T, Zuurbier L, Cauwelier B, Harrison CJ, Schwab C, Pisecker M, Strehl S, Langerak AW, Gecz J, Sonneveld E, Pieters R, Paietta E, Rowe JM, Wiernik PH, Benoit Y, Soulier J, Poppe B, Yao X, Cordon-Cardo C, Meijerink J, Rabadan R, Speleman F, Ferrando A. PHF6 mutations in T-cell acute lymphoblastic leukemiaNature Genetics 2010;42(4):338-42.

- González-García S, García-Peydró M, Martín-Gayo E, Ballestar E, Esteller M, Bornstein R, de la Pompa JL, Ferrando AA, Toribio ML. CSL-MAML-dependent Notch1 signaling controls T lineage-specific IL-7R{alpha} gene expression in early human thymopoiesis and leukemiaThe Journal of Experimental Medicine 2009;206(4):779-91.




Doctoral theses:

Fátima Bayón Calderón"Preclinical targeting of T-ALL relapse using of a novel immunotherapy with anti-pre-TCR CAR-T cells". Science Faculty. Autonomous University of Madrid. Ongoing.

Alba Murcia Ceballos"Study of the oncogenic molecular pathways underlying wild type and mutants IL-7R and T-ALL metabolism". Science Faculty. Autonomous University of Madrid. Ongoing.

- Olga Lancho Medina. "Estudio de la función de SFRP1 en la ontogenia de los linfocitos T y en la patogenia de la leucemia T linfoblástica aguda". Science Faculty. Autonomous University of Madrid. July 2017. Cum laude.

- Mª Jesús García León. "Expression and functional analysis of the Notch signalling pathway within the thymus microenvironment". Science Faculty. Autonomous University of Madrid. January 2016. Cum laude.

Marta Mosquera Sáiz. "Estudio de la contribución de la vía de Notch1 y sus efectores moleculares a la patogénesis de la leucemia T linfoblástica aguda (T-ALL)"Science Faculty. Autonomous University of MadridJuly 2015. Cum laude.

- Sara González García. "Cooperación funcional de Notch1 e IL-7R en el desarrollo de los linfocitos T humanos y en la fisiopatología de la leucemia T linfoblástica aguda". Science Faculty. Autonomous University of Madrid. June 2011. Cum laude.

- Enrique Martín Gayo. "Función tolerogénica, origen y diferenciación de las células dendríticas plasmacitoides residentes en el timo humano". Science Faculty. Autonomous University of Madrid. December 2010. Cum laude.




- "Aplicación terapéutica de agentes inhibidores de CD44 frente a la leucemia linfoblástica aguda (ALL) humana" (Patent ES201231274). María Luisa Toribio, Marina García Peydró and Francisco Sánchez Madrid. Application N.: PCT/ES2013/070576. Country: All. Date: 2013. Organization: UAM y CSIC.

- "Tratamiento terapéutico de leucemias linfoblásticas agudas T y B y linfomas humanos por inhibición del receptor de interleuquina-7 (IL-7R)". María Luisa Toribio, Marina García Peydró, Sara González García, Patricia Fuentes and Juan Alcain. Application N.: PCT/ES2013/070923. Country: All. Date: 2013. Organization: CSIC.

- "Pre-receptor de las células T (Pre-TCR): Caracterización y regulación de su expresión y función durante el desarrollo de las células T en humanos". María Luisa Toribio García, Graciela Carrillo Rosales, Almudena Rodríguez Ramiro, Yolanda Rodríguez Carrasco and Virginia García de Yébenes Mena. Application N.: PCT/ES02/00387. Country: EU/USA.Date: 2002. Organization: CSIC.





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