Monday, 18th December 2017
Cell Biology and Immunology
        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: