Josep Carreras Leukaemia Research Institute

Researchers have demonstrated that some childhood leukemia originate during embryonic development, although they do not manifest after a few months after birth. Researchers from the Institute of Oncology of the University of Oviedo (IUOPA), the Josep Carreras Leukaemia Research Institute, the University of Barcelona and the Centre for Biomedical Research in Cancer Network (CIBERONC) have demonstrated that some childhood leukaemia originate during embryonic development, although they do not manifest after a few months after birth. Acute myeloid leukaemia is the second most common type of acute leukaemia in childhood and can be diagnosed within a few months of life. The early onset of the disease had led to the suspicion that the tumour could have a prenatal origin. However, proving this theory has been challenging due to the lack of prenatal or birth samples. 'The opportunity to study the origin of this leukaemia arose from the case of a five-month-old baby diagnosed with acute myeloid leukaemia at the Hospital Niño Jesús in Madrid,' explains Pablo Menéndez, ICREA professor at the University of Barcelona and the Josep Carreras Institute. 'The parents, who had preserved the umbilical cord blood, opened a line of research that until now had not been possible to address,' adds the researcher. Using precision medicine techniques, researchers analysed the complete genome of the tumour. Unlike tumours in adults, where thousands of mutations are detected, only two chromosomal alterations were identified in this leukaemia. 'Genome analysis allowed us to design a personalised diagnostic method to monitor the disease,' says Xose S. Puente, Professor of Biochemistry at the University of Barcelona. Puente, Professor of Biochemistry and Molecular Biology at the University of Oviedo. 'But these data raise new questions, such as when the tumour arose and in what order these mutations have appeared,' he highlights. These questions are difficult to answer, since such research requires blood samples from the baby before the diagnosis, something that is impossible in the vast majority of cases. However, in this particular case, the existence of a frozen umbilical cord sample allowed researchers to separate different populations of blood cells at birth and to study whether any of the chromosomal alterations detected in the tumour were already present during foetal development. The study revealed that a translocation between chromosome 7 and 12 was already present in some haematopoietic stem cells in the umbilical cord. In contrast, the other chromosomal alteration, a trisomy of chromosome 19, was not present in the foetus, but was found in all tumour cells, suggesting that it contributes to increasing the malignancy of the leukemic cells. 'These data are highly relevant for understanding the development of a devastating disease, and the existence of this umbilical cord sample was crucial to be able for conducting a study that had been impossible until now in acute myeloid leukaemia', adds Talía Velasco, researcher at the Josep Carreras Institute and the University of Barcelona and co-leader of the study. In addition to reconstructing the genomic alterations that the cells undergo to generate this leukaemia, the study has also identified a molecular mechanism that had not been observed before in this type of leukaemia and which causes the activation of a gene, called MNX1, which is frequently altered in this type of tumour. Knowledge of these alterations is essential for developing cell and animal models that allow us to understand the disease's evolution and develop new therapies for treating these pathologies. The study has been led by Xose S. Puente, Professor of Biochemistry and Molecular Biology at the University of Oviedo-IUOPA, Talía Velasco and Pablo Menéndez, from the Josep Carreras Institute and the University of Barcelona, with participation from researchers from four other institutions, including the Hospital Infantil Universitario Niño Jesús, the Hospital Universitario Central de Asturias, the Instituto de Biomedicina y Biotecnología de Cantabria and the Instituto de Investigación Sanitaria La Princesa de Madrid. This research has been made possible thanks to the collaboration of the parents and funding from the Ministry of Science, Innovation and Universities, the European Research Council, the AECC Scientific Foundation, the Foundation Unoentrecienmil, the "La Caixa" Foundation, the Government of Catalonia, CIBERONC and the III Health Institute.

Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. A new study reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. Defects in the blood vessel network of the central nervous system have been linked to early symptoms of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis (ALS). It is this complex vascular network that provides the necessary nutrients -- especially glucose and oxygen -- to activate all neuronal functions. Now, a study led by the University of Barcelona and the Bellvitge Biomedical Research Institute (IBIDELL) reveals that the TDP-43 protein is essential for forming a stable and mature blood vessel network in the central nervous system. According to the study, featured on the cover of the journal JCI Insight, the TDP-43 protein is also critical in maintaining the integrity of the blood-brain barrier, which prevents toxins and pathogens from reaching the central nervous system. The project is led by Professor Eloi Montañez, from the Faculty of Medicine and Health Sciences of the University of Barcelona and IDIBELL, and involves teams from the Faculty of Biology and the Institute of Biomedicine of the UB (IBUB), the Josep Carreras Leukaemia Research Institute, and the National Centre for Genomic Analysis (CNAG-CRG). What is the role of the TDP-43 protein in the vascular system? The TDP-43 protein is a key factor in nervous system function and neuronal plasticity. It is a DNA- and RNA-binding protein that regulates gene expression, and its dysfunction has been associated with various neurodegenerative disorders. Although much progress has been made recently in understanding the functions of TDP-43 in neurons, its exact role in the endothelial cells that make up the circulatory system, the formation of new blood vessels (angiogenesis) and vascular function was not yet known. "The study reveals for the first time that TDP-43 is essential for the formation and stability of blood vessels in the central nervous system, and for the integrity of the blood-brain barrier," says Professor Montañez, from the UB's Department of Physiological Sciences. The vascularization of the central nervous system and the formation of the blood-brain barrier are regulated by different signalling pathways. For example, the integrin signalling pathway that regulates the interaction of cells with the extracellular matrix and the signalling carried out by the transcription factor β-catenin. "In the study, we found that TDP-43 deficiency alters the extracellular matrix that surrounds blood vessels and reduces β-catenin signalling in endothelial cells," says the researcher. "Thus, mice without endothelial TDP-43 protein show multiple haemorrhages and vascular degeneration in the brain and spinal cord." Vascular defects and inflammatory response in neurosciences The authors also identify TDP-43 in endothelial cells as a potential contributing factor to the vascular defects that trigger the inflammatory response observed in patients diagnosed with TDP-43-associated diseases. "Some alterations in the blood vessels of the central nervous system -- defects in the integrity of the blood-brain barrier or degeneration of endothelial cells -- are associated with inflammatory and immune responses that can cause neuronal loss. This process of neuronal degeneration underlies the origin or progression of various neurological disorders -- stroke, diabetic retinopathy -- and some neurodegenerative diseases such as Alzheimer's disease, ALS or LATE (Limbic-predominant age-related TDP- 43 encephalopathy). The study will help to better understand the molecular mechanisms linking vascular defects and neuroinflammation. "Our goal now is to analyse whether defects in TDP-43 protein function in the endothelium of mature vessels could be involved in ALS or other TDP-43-associated pathologies due to increased vascular permeability or inflammatory processes," Montañez concludes.

New research identifies the class II PI3K-C2b protein, a member of the PI3 family of kinases, as one of the key regulators of blood vessels growth in humans and other mammals. Mutations in these family of proteins may lead to vascular malformations and the precise understanding of the whole process is instrumental in opening the door to new therapeutic approaches in the future. Blood vessels are responsible of the appropriate and efficient delivery of nutrients and oxygen to the whole body. To do so, they must grow and branch to reach every cell in a process called angiogenesis. The precise regulation of the sprouting and pruning of blood vessels is complex and partly unknown, but endothelial cells, those lining the inner part of the vessels, are known to play an important role. The growth and proliferation of endothelial cells is promoted by a protein known as mTORC1. Controlling its activity is important to organise a coherent branching of blood vessels and alterations in this process may lead to vascular malformations. New research from the Mariona Graupera's lab (Josep Carreras Leukaemia Research Institute), published yesterday at the top journal Science Signaling, has just found that PI3K-C2b, a family member of the PI3K kinases, is responsible of the mTORC1 fine tuning through its inhibition. In a series of experiments using mice models and human cells, researchers found that animals with an inactive form of PI3K-C2a displayed aberrantly enlarged blood vessels. Similarly, when PI3K-C2b was transiently inactivated, endothelial cells appeared larger than usual. Both effects correlated with an increased expression of mTORC1 and were restored upon its external repression. The findings are important since mutations in components of the PI3K family of proteins are frequent in patients with congenital vascular disorders. Understanding the link between one and the other may be useful to find new therapeutic targets in the future. The present work was a collaborative initiative including researchers from the Josep Carreras Leukaemia Research Institute, the CNIO, the Universitätsmedizin Berlin, the Max Delbrück Center for Molecular Medicine in the Helmholtz Association and the University College London. Funders of the project were the Spanish Ministry for Science and Innovation, the PTEN Foundation, "La Caixa" Foundation, the Spanish Association Against Cancer and the BBVA Foundation.