Development of the human lymphohematopoietic system
Research summary:
We are interested in understanding the mechanisms that control cell-lineage fate decisions of hematopoietic progenitor cells in humans, with special focus on the identification of cellular and molecular players involved in T-cell commitment and differentiation in the human thymus. Main current goals are: 1) deciphering the particular microenvironments and molecular pathways involved in T and non-T developmental programs of thymus-seeding progenitors; 2) identifying molecular effectors of physiological T-cell development whose dysregulation results in T-cell acute lymphoblastic leukemia (T-ALL), with the ultimate goal of developing specific targeting therapies; and 3) characterizing molecular 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.
Our loss- and gain-of-function genetic approaches, in vitro and in vivo cell differentiation assays and humanized mouse models of disease have shown that spatiotemporal regulation of signaling through the Notch1 pathway guides the formation of particular thymus niches supporting the specification of distinct T and non-T human hematopopietic lineages. Notch1 also emerged as a key regulator of thymic epithelial cell homeostasis that controls the age-associated functional decline of thymus microenvironment, and the emergence of immunosenescence. Our results have also highlighted the prevalent role that Notch1 signaling plays in both physiological and pathological human T-cell development. Moreover, the oncogenic impact of Notch1 in a novel in vivo model of human T-ALL generation from normal hematopoietic progenitors provided critical information of key Notch1 targets specifically mediating: 1) the expansion of normal and pathological pre-T cells, and 2) the interaction of pre-leukemic T-ALL cells with the bone marrow microenvironment, as a mandatory step for leukemia-initiating cell generation and progression. Collectively, our data highlight the relevance of Notch1 target manipulation as a promising therapeutic strategy for T-ALL, providing proof of concept that our novel immunotherapeutic approaches validated in preclinical models are suitable for later translation to the clinic.
Figure-1: Expression of DLL1 Notch ligand in human tonsil. DLL1: Delta-like ligand 1. GC: Germinal Centre.
Figure-2: Analysis of in vivo tumor progression of luciferase-expressing human primary T-ALL cells upon xenotrasplantation into immunodeficient mice.
| Last name | Name | Laboratory | Ext.* | Professional category | |
|---|---|---|---|---|---|
| Alcaín Sánchez | Juan | 222 | 4588 | jalcain(at)cbm.csic.es | Titulado Medio de Actividades Tecn.y Prof.GP2 |
| Aparicio Valencia | Ángela | 222 | 4588 | M2 | |
| Castillo Gutiérrez | Eloisa | 222 | 4588 | eloisa.castillo(at)cbm.csic.es | E.Ayudantes De Invest. De Los Oo.Publicos De Investigacion |
| Cela Rodríguez | Carmela | 222 | 4588 | ccela(at)cbm.csic.es | Titulado Sup. Actividades Tecn. y Prof.GP1 |
| Fuentes Villarejo | Patricia | 222 | 4588 | pfuentes(at)cbm.csic.es | Doctor FC3 |
| García Peydró | Marina | 222 | 4588 | mgpeydro(at)cbm.csic.es | Titulado Sup. Actividades Tecn.y Prof.GP1 |
| Pérez Fernández | Raquel Victoria | 222 | 4588 | rvperez(at)cbm.csic.es | M3 Predoc.formación |
| Toribio García | María Luisa | 222 | 4556 | mtoribio(at)cbm.csic.es | E. Profesores de Investigación de Organismos Públicos de Investigación |
Relevant publications:
- 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;134(24):2171-2182.
- 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 development. Development 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.
- 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 ML. Modeling altered human T-cell development. Blood 2016;128(6):743-5.
- 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 fate. Leukemia 2015;29(8):1741-53.
- 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 development. Nucleic Acids Research 2015;43(2):760-74.
Doctoral theses:
- Fátima Bayón Calderón. "Preclinical targeting of T-ALL relapse using of a novel immunotherapy with anti-pre-TCR CAR-T cells". Facultad de Ciencias. Universidad Autónoma de Madrid. En desarrollo.
- Alba Murcia Ceballos. "Study of the oncogenic molecular pathways underlying wild type and mutants IL-7R and T-ALL metabolism". Facultad de Ciencias. Universidad Autónoma de Madrid. En desarrollo.
- 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". Facultad de Ciencias. Universidad Autónoma de Madrid. Julio 2017. Sobresaliente cum laude.
- Mª Jesús García León. "Expression and functional analysis of the Notch signalling pathway within the thymus microenvironment". Facultad de Ciencias. Universidad Autónoma de Madrid. Enero 2016. Sobresaliente 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)". Facultad de Ciencias. Universidad Autónoma de Madrid. Julio 2015. Sobresaliente 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". Facultad de Ciencias. Universidad Autónoma de Madrid. Junio 2011. Sobresaliente cum laude.
- Enrique Martín Gayo. "Función tolerogénica, origen y diferenciación de las células dendríticas plasmacitoides residentes en el timo humano". Facultad de Ciencias. Universidad Autónoma de Madrid. Diciembre 2010. Sobresaliente cum laude.
Patents:
- ”Aplicación terapéutica de agentes inhibidores de CD44 frente a la leucemia linfoblástica aguda (ALL) humana” (Patente ES201231274). María Luisa Toribio, Marina García Peydró y Francisco Sánchez Madrid. N. de solicitud: PCT/ES2013/070576. País de prioridad: Todos. Fecha de prioridad: 2013. Entidad titular: 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 y Juan Alcain. N. de solicitud: PCT/ES2013/070923. País de prioridad: Todos. Fecha de prioridad: 2013. Entidad titular: 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 y Virginia García de Yébenes Mena. N. de solicitud: PCT/ES02/00387. País de prioridad: EU/USA. Fecha de prioridad: 2002. Entidad titular: CSIC.
