On 17 November last, in the year that the Pfizer Awards celebrate their 55th anniversary, three research projects were given awards: two projects in Basic Research and one in Clinical Research.

Basic Research Awards:

Project: “Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36” Authors: Sérgio Fernandes Almeida and Maria Carmo-Fonseca

A recent finding that has been gaining roots is that transcription – the mechanism by which the code contained in genes is copied into a messenger RNA (mRNA) – is influenced by a class of proteins called histones. The histones associate to genes forming structures similar to the “beads of a necklace”. Those “beads” may undergo several chemical changes that confer them distinct functional properties. The mRNA maturation (splicing) that occurs during transcription is one of the events affected by histone alteration. However, the opposite effect, whereby splicing could also influence the modification of histones had not yet been investigated.

Thanks to the help of advanced genomic analysis techniques applied to human cells and mice, we were able to observe that, during transcription, slicing induces a specific change in the histones of transcription genes. These genes thus start to present a specific signal as a result of the presence of those modified histones. Controlling this signal is paramount to enable gene expression programmes to be properly executed and controlled by the cells.

“Changes in these mechanisms are at the origin of many diseases, cancer being the one that has attracted greater attention from researchers”. 

Project: “CLASPs ensure spindle pole integrity and prevent irreversible multipolarity in response to kinetochore traction forces”
Authors: Elsa Logarinho and Helder Maiato

In cell division, the fidelity of the distribution of genetic material by the two daughter cells depends on the formation of a bipolar structure – the mitotic spindle. In this work, we have identified a new molecular mechanism necessary for the stability of the mitotic spindle which involves a type of protein called CLASPs. The functional disorder of these molecules leads to the formation of abnormal multipolar spindles that result in uneven distribution of genetic material, jeopardizing the viability of the daughter cells. This mechanism may be explored in cancer therapy, which is characterised by uncontrolled division of cells.

Project: “Oncogenic IL7R gain-of-function mutations in childhood T-cell acute lymphoblastic leukemia”
Author: João Barata

T-cell acute lymphoblastic leukaemia is a blood cancer especially common in children and which is characterised by uncontrolled increase in the number of T lymphocytes (which are white blood cells specific to our immune system). Our study has identified a number of mutations so far unknown which are present in about 9% of leukaemia patients studied, and demonstrated that these mutations may be at the origin of the same type of tumours. The mutations that have now been identified occur in a gene that codes for a protein located on the surface of T cells, called interleukin-7 receptor. This protein is distributed along the cell surface and is in contact both with the exterior and the interior, thus providing a link passage of chemical information from outside to inside the cell. This transfer of information occurs when another protein that circulates in the bloodstream called interleukin-7 binds to the receptor on the surface of T cells. The binding of interleukin-7 to its receptor triggers a series of reactions inside the cell which, under physiological conditions, are essential for the normal development and multiplications of T cells. Our research has allowed us to find that cancer cells of some paediatric patients with leukaemia contain a mutated receptor, and the mutation of the receptor causes it to fail to require external information, that is, the binding of interleukin-7, in order to promote cell multiplication. As a result, T cells multiply uncontrollably, causing a tumour.
In addition to characterising the way mutations occur leading to the growth of leukaemia, we also identified a set of drugs that have already been tested in other diseases, such as rheumatoid arthritis, which can be effective in eliminating the effect of mutations, leading to the death of the cells that have them. In short, this study not only identified mutations in a gene that is crucial to the immune system and which are associated to the development of childhood leukaemia, but also advanced potential future therapeutic uses as a result of this finding.

The presentation and award giving ceremony was chaired by H.E. the Minister of Health, Dr. Paulo Macedo, and took place on 17 November last at the Aula Magna of the Faculty of Medicine of the University of Lisbon. It was attended by the Secretary of State for Science, Professor Leonor Parreira, the Director of the Faculty of Medicine of the University of Lisbon, Professor J. Fernandes e Fernandes, the Elected-President of the Society of Medical Sciences of Lisbon, Professor José Miguel Caldas de Almeida, the Secretary General of the Society of Medical Sciences of Lisbon, Professor Luís Graça, and by the Chief Executive Officer of Pfizer, Dr. Ana Paula Carvalho.

Editorial Team
news@fm.ul.pt