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AGE-RELATED CHANGES IN HEMATOPOIESIS

Periodic Reporting for period 1 - ARCH (AGE-RELATED CHANGES IN HEMATOPOIESIS)

Reporting period: 2019-06-01 to 2021-05-31

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 so far 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 is the main focus of ARCH (Age-Related Changes in Hematopoiesis). By using integrate genetic, epigenetic, cellular and genomic approaches, ARCH studies the molecular mechanisms governing physiological changes of hematopoiesis throughout life and their correlation with pathological conditions, with the final goal to develop novel therapeutic strategies.
Hematopoietic stem cells (HSCs) represent a rare population, residing in the Bone Marrow (BM), at the top of a hierarchy of cells that ultimately generate all mature blood cells. This process requires the fine-tuned balanced production of multipotent progenitors, which progressively restrict their potential and acquire a defined cell fate. With ageing, HSCs accumulate DNA mutations that lead to tissue degeneration and malignant transformation. The ARCH research contributed to the profiling of the phenotypic and functional properties of young versus old HSCs. This analysis led to the identification of genes that play a role in maintaining genome integrity and therefore 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 these genes (and their mutations) on preleukemic and leukemic conditions. The progressive lineage specification and differentiation process is controlled by a fine forward-and-feedback crosstalk between extrinsic signals from the bone marrow niche and intrinsic factors that entail the expression of a repertoire of specific transcription factors, epigenetic modifiers, microRNA, long-noncoding-RNA and splicing factors. Among these key players, ARCH focused on transcriptional, posttranscriptional and epigenetic regulators involved in normal blood cells differentiation and in leukemias.
The growth of leukemic cells is sustained by signaling pathways that promote their expansion. ARCH focused on characterization of the properties of human and mouse blood cells from subjects of different ages and on their molecular bases. ARCH studied genes (including Ikaros family genes, integrins, demethylation/methylation genes, transcription factors, chromatin regulators), pathways (CXCL2/CXCR4; TSRPL/IL7RA/JAK; JAK/STAT), and epigenetic signatures (methylation status) in normal and leukemic cells, with a specific focus on the genetic vulnerability in Down syndrome subjects. ARCH research led to the characterization of these genes and signaling pathway as possible therapeutic targets and to the generation of cellular and in vivo models of leukemia for the testing of novel drugs and/or drugs combinations.
ARCH studies required the combination of transcriptomics, functional genomics, and the generation of cellular and in vivo models of premalignant/malignant cells to test novel therapeutic molecules/treatments. Through the development of these experimental approaches, ARCH students challenged themselves in the solving of complex scientific and technical problems. The parallel training in complementary skills organized by ARCH, dealing with the social and ethical implication of biomedical research, further enriched the ESRs scientific and personal growth.
Primary leukemic cells in colonies generated from clonogenic assays with ckit progenitors transforme