[FPI2019] Biomedicina

Leukemia accounts for a third of all cancers in children and its incidence has increased in the last 20 years. Hence childhood leukemia arose to a “modern life-style” malignancy making preventive strategies as important as any therapy improvement.Recent results have shown that around 5% of healthy children carry a preleukemic clone. These preleukemic cells can persist for years, without harm for the individual and it is the exposure to an oncogenic environment, which provides the necessary selection pressure for the acquisition of secondary genomic alterations and leukemia outgrowth. However, these oncogenic environments are not known. In the recent years, our group has discovered for the first time the causal relationship between childhood B-cell leukemia (B-ALL) development and exposure to natural infections, implying that childhood B-ALL may be a preventable cancer (Cancer Discovery-2015; Nature-2017; Cancer Research-2017; Cancer Research-2018; EMBOJ-2018, Leukemia-2018; Trends in Cancer-2018).

The need for the clarification how genetic predisposition and exposure to infection act synergistically in B-ALL development is one of the current major goals and challenges in Oncology. However, as of today, we cannot distinguish pre-leukemic cells that might evolve to cancer from those that never progress to B-ALL because the molecular events involved in the conversion of a pre-leukemic clone in an irreversible transformed state as a result of infection exposure have been particularly elusive in children. Therefore, preclinical models of childhood B-ALL as a result of infection exposure have been an essential unmet need to prevent the occurrence of this disease. A novel and unique feature of this proposal is the availability of mouse models  for both the ETV6-RUNX1 and the Pax5-inherited susceptibility which only develop human-like B-ALL as a result of natural infection exposure. These mouse models have anticipated the second hit in childhood B-ALL for the first time and they will be used by our research team as the basis for understanding the molecular mechanisms that govern the development of B-ALL as a result of natural infection exposure. Now, state-of-the-art genetic and genomic approaches will be used to define the (epi)genetic and inmune events arising from leukemic reprogramming of  pre-leukemic cells by the genetic predisposition–infection exposure interaction. The conceptual and mechanistic insights obtained in this experimental system represent an entirely novel strategy and the results of these endeavours will inform approaches for preventing  childhood B-ALL.

Tema: Infectious trigger in childhood pB-ALL – deciphering the mechanisms responsible for clonal evolution with the aim of leukemia prevention 

Referencia: RTI2018-093314-B-I00

Correo: isg@usal.es