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Periodic Reporting for period 2 - ARCH (AGE-RELATED CHANGES IN HEMATOPOIESIS)

Reporting period: 2021-06-01 to 2023-11-30

An estimated 80 millions people are currently affected by blood disorders in Europe. The clinical management of hematological diseases represents for the European Healthcare a serious medical challenge and an important socio-economical burden, which is expected to increase in the next few years, because of the increased longevity of the European population. Even more important, hematological disorders have a high impact on the quality of life of patients and their families.
Ageing is associated with an increased risk of acquiring various blood disorders, either malignant (myelodysplastic syndromes, myeloma, lymphomas) or non-malignant (such as anemias, primary immunodeficiency and coagulation disorders). Other blood disorders occur most often in children and are different from those seen in adults. The different incidence of different blood disorders at different ages suggests that they might reflect and undergo, in their onset and evolution, age-related changes in hematopoiesis, in a largely unknown manner. Many crucial questions remain unanswered. How does blood composition change as we age? Do these physiological changes have an impact on hematological diseases? The answer to these questions was the main focus of ARCH (Age-Related Changes in Hematopoiesis), whose ultimate goal was the characterization of key factors that trigger hematological diseases in distinct age groups and the identification of strategies for delaying or preventing their onset.
The effort in this direction was made possible by putting together a network of 15groups from 10 Countries working on different -yet complementary- aspects of hematopoiesis, belonging to both academic and private sectors. The rich portfolio of expertise and its collaborative sharing within the network allowed to develop specific cellular and in vivo models, experimental approaches based on cutting edge technologies including transcriptomics, functional genomics and epigenetics.
The above challenges require a multidisciplinary approach that can be tackled only by scientists able to deal with this level of complexity. ARCH enrolled 15 young researchers from 7 countries. Through the development of their research projects, ARCH students challenged themselves in the solving of complex scientific and technical problems. Their parallel training in complementary skills, dealing with the social and ethical implication of biomedical research, further enriched their scientific and personal growth. We believe that ARCH students will contribute fruitfully to European research, economy and society.
ARCH focused on three primary themes impacting on aging of the hematopoietic system, namely the mechanisms of physiological ageing, the role of specific genetic and epigenetic pathways governing hematopoietic differentiation, and the altered signaling within the bone marrow niche, which ultimately sustains preleukemia and leukemia cells. ARCH research contributed to the profiling of the phenotypic and functional properties of young versus old Hematopoietic Stem Cells (HSCs), a rare cell population, residing at the top of a hierarchy of cells that, through progressive differentiation, generate all mature blood cells. With ageing, HSCs accumulate DNA mutations that lead to tissue degeneration and malignant transformation. ARCH identified specific HSCs subpopulations, genes and epigenetic signatures that contribute to HSCs fitness. This task first required the set-up of specific protocols for the study of small numbers of cells and the generation of in vitro and in vivo models to study the impact of the identified genes (and their mutations) on preleukemic and leukemic conditions. Aged population is more vulnerable to infections and malignancies because of a defective immune response. In order to identify common trends and differences in human hematopoietic ageing, a reference panel of immune cells populations in healthy individuals of different ages and sexes has been generated and made available to the hematologists community.
HSCs progressively differentiate into different blood cell types. ARCH focused on the identification of genes, epigenetic factors and cellular processes whose alteration lead to the development of hematological diseases, particularly of myeloid leukemias. Identifying these factors is crucial for discovering novel biomarkers, indicators of disease progression, genetic dependencies, and potential treatment targets. Finally, signals within the bone marrow niche sustain preleukemia and leukemia progression and can contribute to resistance to conventional therapy. These studies necessitated the generation of cellular and in vivo models of leukemia, enabling the dissection of signal transduction axes that ultimately promote leukemia cell growth and their crosstalk. The identification of specific genes and vulnerabilities of leukemia cells is pivotal to the development of low-toxicity, high-efficacy therapies and combinatorial therapies with a better potential to prevent relapse.
The results obtained by ARCH were shared with scientific community through publications in international journals (19) so far, with the majority of them expected in the next 1-2 years), their presentation into national and international scientific meeting by both the PIs and the ARCH fellows. ARCH results were also presented to lay public through the ARCH website and through specific initiatives, culminated in the participation of all ARCH students to the European researcher’s night. Moreover, during ARCH, students were trained to use different media (cartoons, short videos) to present the content of their research and to increase social awareness on the value of research for the society.
The overall objective of ARCH was manifold:
The main scientific goal was a better knowledge of hematopoiesis. The ARCH research led to a better understanding of the molecular mechanisms governing hematopoietic differentiation and their changes during physiologically aging and in pathological conditions. Successfully determining the extent to which physiological evolution influences the preferential onset of age-specific diseases will enable their prevention and the design of more effective targeted therapies.
A second important objective was to contribute to the formation of a new generation of young scientists capable of addressing complex problems and working collaboratively on an international level. These scientists will actively contribute to the future growth of European science, both in the academic and in the private sector, building on the portfolio of experiences and knowledge acquired through ARCH. We are confident that collaborations initiated through ARCH will remain robust beyond the project's duration. Finally, we are convinced that the personal and human experience of exchange, collaboration, and sharing promoted by ARCH is a valuable asset for all ARCH participants, especially for the younger ones who, for the first time, had this opportunity.
ARCH Network - Closing Conference