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.
