Cabecera 2019 CBMSO CSIC UAM

Sunday, 25th August 2019

Cellular plasticity in development and cancer


Grupo-400

 


César Cobaleda

ASciStaff

APublications

 

Research Summary:

Research in our group is focused on the study of cellular plasticity in the hematopoietic system and how it is controlled in pathological conditions (cancer and developmental syndromes). As experimental tool we use genetically engineered mouse models (GEMMs) in which we modify the levels and windows of expression of transcription factors and epigenetic regulators, either normal or oncogenic.

The cancer stem cell (CSC) model suggests that the genetic information responsible for tumor generation might only be required at the level of these CSCs. We have generated GEMMs expressing, in their hematopoietic stem cells, the oncogenic lesion responsible for the initiation of childhood precursor B acute lymphoblastic leukemias (pB-ALLs). With these models, we are studying the role that the exposure to different agents (electromagnetic fields, other genetic lesions, infections) might play in the development of pB-ALLs, and we have demonstrated that exposure to infections can be one of the triggering factors.

 

figure 1

FIGURE 1: DESIRED CHARACTERISTICS FOR AN IDEAL pB-ALL GEMM. (A) When exposed to environmental agents, WT mice do not develop human-like spontaneous pB-ALLs. (B) Conventional GEMMs that do not take into account the human pB-ALL cell-of-origin fail to generate human-like pB-ALL, although they give rise to different types of haematopoietic malignancies. (C) The successful generation of GEMMs developing human-like pB-ALL requires taking into account the nature of the leukemic cell-of-origin in humans (most likely in the bone marrow), and to consider that leukemias arise from a few cells in the context of a normal tissue. These mice might develop human-like pB-ALL, and the incidence, onset or pathogenicity of the disease should increase in the presence of any real leukemia-inducing environmental agent.

 

Wolf Hirschhorn Syndrome (WHS) is caused by a deletion in chromosome 4. WHS patients present many severe problems, including immunodeficiencies. One of the deleted genes is WHS-Candidate 1 (WHSC1), an epigenetic regulator involved in DNA damage repair and whose overexpression is also implicated in multiple myeloma and pB-ALL. We are studying the exome of WHS patients to try and determine if they accumulate DNA damage as a consequence of the partial loss of WHSC1, which could make them more susceptible to tumor development. We have characterized hematopoietic development and immune function in Whsc1 knockout mice, and therefore we have a new model recapitulating patient’s immunodeficiencies. In this way, combining the study of human patient samples with the data from advanced mouse models, we hope to identify the molecular mechanisms behind the alterations affecting WHS patients. This would allow us to improve their medical attention and to have a prognostic capacity regarding their potential susceptibility to genetic damage.

 

figure 2

FIGURE 2. PRIVATE VARIANTS IDENTIFIED IN THE ANALYSIS OF THE EXOMES OF WOLF-HIRSCHHORN SYNDROME PATIENTS.. Private variants (with low population frequency and 0/1 genotype) for the analysed patients, plotted along the chromosomes.

 

 

Publications:

  • Campos-Sanchez E, Deleyto-Seldas N, Dominguez V, Carrillo-de-Santa-Pau E, Ura K, Rocha PP, Kim JH, Aljoufi A, Esteve-Codina A, Dabad A, Gut M, Heyn H, Kaneda Y, Nimura K, Skok JA, Martinez-Frias ML, Cobaleda C. (2017) Wolf-Hirschhorn Syndrome Candidate-1 is necessary for correct hematopoietic and B cell development. Cell Reports, http://dx.doi.org/10.1016/j.celrep.2017.04.069
  • Robles EF, Mena-Varas M, Barrio L, Merino-Cortes SV, Balogh P, Du MQ, Akasaka T, Parker A, Roa S, Panizo C, Martin-Guerrero I, Siebert R, Segura V, Agirre X, Macri-Pellizeri L, Aldaz B, Vilas-Zornoza A, Zhang S, Moody S, Calasanz MJ, Tousseyn T, Broccardo C, Brousset P, Campos-Sanchez E, Cobaleda C, Sanchez-Garcia I, Fernandez-Luna JL, Garcia-Muñoz R, Pena E, Bellosillo B, Salar A, Baptista MJ, Hernandez-Rivas JM, Gonzalez M, Terol MJ, Climent J, Ferrandez A, Sagaert X, Melnick AM, Prosper F, Oscier DG, Carrasco YR, Dyer MJ, Martinez-Climent JA. (2016) Homeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics. Nat Commun. 7:11889.
  • Gong Y, Capstick M, Dasenbrock C, Fedrowitz M, Cobaleda C, Sánchez-García I, Kuster N. (2016) Comparative dosimetry for children and rodents exposed to extremely low-frequency magnetic fields. Bioelectromagnetics. 37:310-322.
  • Schüz J, Dasenbrock C, Ravazzani P, Röösli M, Schär P, Bounds PL, Erdmann F, Borkhardt A, Cobaleda C, Fedrowitz M, Hamnerius Y, Sanchez-Garcia I, Seger R, Schmiegelow K, Ziegelberger G, Capstick M, Manser M, Müller M, Schmid CD, Schürmann D, Struchen B, Kuster N. (2016) Extremely low-frequency magnetic fields and risk of childhood leukemia: A risk assessment by the ARIMMORA consortium. Bioelectromagnetics 37: 183-189.
  • Auer F, Ingenhag D, Bhatia S, Enczmann J, Cobaleda C, Sanchez-Garcia I, Borkhardt A, Hauer J. (2016) GEMMs addressing Pax5 loss-of-function in childhood pB-ALL. Eur J Med Genet. 59:166-172.
  • Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, Auer F, González-Herrero I, García-Ramírez I, Ginzel S, Thiele R, Constantinescu SN, Bartenhagen C, Dugas M, Gombert M, Schäfer D, Blanco O, Mayado A, Orfao A, Alonso-López D, Rivas Jde L, Cobaleda C, García-Cenador MB, García-Criado FJ, Sánchez-García I, Borkhardt A. (2015) Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility. Cancer Discov. 5:1328-1343.

 


 

Other activities:

  • National Award for Research in the field of Rare Diseases 2015, awarded by the Spanish Federation of Rare Diseases (FEDER).
  • “Ad hoc” member of the committee of the German Federal Office for Radiation Protection (BfS), in charge of defining future research programs on the role of environmental factors in the pathogenesis of childhood leukemia.

 


 

More links about our work:

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:

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: