CELLULAR PLASTICITY IN LEUKEMIA

B-cell acute lymphoblastic leukemia (B-ALL) is the most common form of childhood cancer. Interestingly, almost 5% of all newborn children present some form of congenital genetic predisposition to develop B-ALL; luckily, very few (<1%) of these predisposed children will progress to B-ALL, by suffering a second hit that leads to full-blown disease. The causes that trigger this progression are still unclear, but B-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. A stress on the immune system has been postulated to be involved in the progression to B-ALL, and this stress could be triggered by exposure to common infections (under certain circumstances), or by other stressors like antibiotics, diet, or alterations in the microbiota. Therefore, understanding the interaction between the immune stress and the preleukemic cells existing in so many newborns could provide us with strategies aimed at preventing childhood B-ALL.
We have generated mice expressing the oncogenic lesions responsible for the initiation of childhood B-ALLs, and we have demonstrated that common infections are indeed one of the main triggering factors leading to leukemia development. Furthermore, we have shown that preventive pharmacological treatment of predisposed mice with inhibitors of oncogenic signaling pathways protects them from the appearance of the disease, showing that B-ALL could be a preventable disease. Since the presence of latent premalignant cells is a common characteristic of many types of cancers, our results offer a general proof-of-principle for the development of similar preventive strategies for other malignancies.

CELLULAR PLASTICITY IN IMMUNODEFICIENCIES

Wolf Hirschhorn Syndrome (WHS) is a complex rare disease caused by the loss of genetic material in the “p” arm of chromosome 4, and affected patients present many severe problems, including life-threatening immunodeficiencies. One of the genes affected in WHS is WHS-Candidate-1 (WHSC1), an epigenetic regulator involved in many processes affecting genome function and that, interestingly, is also mutated in childhood B-ALLs and other malignancies of B-cell origin like Multiple Myeloma (where it is called “Multiple Myeloma SET domain protein”, MMSET). We are using genetically engineered mouse models with deregulated Whsc1 function to gain insight into the molecular biology of WHS-associated hematopoietic pathologies, in order to better understand the role of epigenetics in normal and aberrant hematopoietic development, and to develop future prospective therapeutic interventions. We have shown that the loss of Whsc1 is essential for the normal differentiation and function of B cells, therefore experimentally linking it to the immunodeficiency of WHS patients, and generating a preclinical model for therapy development.

CELLULAR PLASTICITY IN MULTIPLE MYELOMA

We have collaborated in the generation of new MMSET-based multiple myeloma mouse models recapitulating the characteristics of the human disease and showing a correlation between the genetic and immunological characteristics of each tumor and its response to preclinical therapies, therefore enabling the prediction of treatment outcomes with next-generation immunotherapies.