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.

Image

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

Image

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

Image


* For external calls please dial 34 91196 followed by the extension number
Last nameNameLaboratoryExt.*e-mailProfessional category
Alcaín SánchezJuan2224588jalcain(at)cbm.csic.esColaborador GP2
Bayón CalderónFátima2224588fbayon(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Cela RodríguezCarmela2224588ccela(at)cbm.csic.esInvestigador GP1
Fuentes VillarejoPatricia2224588pfuentes(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
García PeydróMarina2224588mgpeydro(at)cbm.csic.esInvestigador GP1
González GarcíaSara2224588sgonzalez(at)cbm.csic.esTitulado Sup. Actividades Tecn. y Prof.GP1
Murcia CeballosAlba2224588amurcia(at)cbm.csic.esColaborador GP2
Toribio GarcíaMaría Luisa2224556mtoribio(at)cbm.csic.esE. 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 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 modelThe 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 fateLeukemia 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 developmentNucleic 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.

NOTE! This site uses cookies and similar technologies.

If you not change browser settings, you agree to it. Learn more

I understand

COOKIES POLICY

What are cookies?

A cookie is a file that is downloaded to your computer when you access certain web pages. Cookies allow a web page, among other things, to store and retrieve information about the browsing habits of a user or their equipment and, depending on the information they contain and the way they use their equipment, they can be used to recognize the user.

Types of cookies

Classification of cookies is made according to a series of categories. However, it is necessary to take into account that the same cookie can be included in more than one category.

  1. Cookies according to the entity that manages them

    Depending on the entity that manages the computer or domain from which the cookies are sent and treat the data obtained, we can distinguish:

    • Own cookies: those that are sent to the user's terminal equipment from a computer or domain managed by the editor itself and from which the service requested by the user is provided.
    • Third party cookies: those that are sent to the user's terminal equipment from a computer or domain that is not managed by the publisher, but by another entity that processes the data obtained through the cookies. When cookies are installed from a computer or domain managed by the publisher itself, but the information collected through them is managed by a third party, they cannot be considered as own cookies.

  2. Cookies according to the period of time they remain activated

    Depending on the length of time that they remain activated in the terminal equipment, we can distinguish:

    • Session cookies: type of cookies designed to collect and store data while the user accesses a web page. They are usually used to store information that only is kept to provide the service requested by the user on a single occasion (e.g. a list of products purchased).
    • Persistent cookies: type of cookies in which the data is still stored in the terminal and can be accessed and processed during a period defined by the person responsible for the cookie, which can range from a few minutes to several years.

  3. Cookies according to their purpose

    Depending on the purpose for which the data obtained through cookies are processed, we can distinguish between:

    • Technical cookies: those that allow the user to navigate through a web page, platform or application and the use of different options or services that exist in it, such as controlling traffic and data communication, identifying the session, access to restricted access parts, remember the elements that make up an order, perform the purchase process of an order, make a registration or participation in an event, use security elements during navigation, store content for the broadcast videos or sound or share content through social networks.
    • Personalization cookies: those that allow the user to access the service with some predefined general characteristics based on a series of criteria in the user's terminal, such as the language, the type of browser through which the user accesses the service, the regional configuration from where you access the service, etc.
    • Analytical cookies: those that allow the person responsible for them to monitor and analyse the behaviour of the users of the websites to which they are linked. The information collected through this type of cookies is used in the measurement of the activity of the websites, applications or platforms, and for the elaboration of navigation profiles of the users of said sites, applications and platforms, in order to introduce improvements in the analysis of the data of use made by the users of the service.

Cookies used on our website

The CBMSO website uses Google Analytics. Google Analytics is a simple and easy to use tool that helps website owners to measure how users interact with the content of the site. You can consult more information about the cookies used by Google Analitycs in this link.

Acceptance of the Cookies Policy

The CBMSO assumes that you accept the use of cookies if you continue browsing, considering that it is a conscious and positive action from which the user's consent is inferred. In this regard, you are previously informed that such behaviour will be interpreted that you accept the installation and use of cookies.

Knowing this information, it is possible to carry out the following actions:

  • Accept cookies: if the user presses the acceptance button, this warning will not be displayed again when accessing any page of the portal.
  • Review the cookies policy: the user can access to this page in which the use of cookies is detailed, as well as links to modify the browser settings.

How to modify the configuration of cookies

Using your browser you can restrict, block or delete cookies from any web page. In each browser the process is different, here we show you links on this particular of the most used browsers: