Periodic Reporting for period 1 - SENAGE (Senescence as a key factor in leukemogenesis and bone marrow homeostasis in aging)
Reporting period: 2021-09-01 to 2023-08-31
Cancer is a significant health concern and a leading cause of death worldwide. In Europe, and the United States, it stands as the second leading cause of death. While cancer can affect people at any age, getting older is a major risk factor. Aging is a complex process where our bodies gradually decline in function, and changes in how our genes are regulated, called epigenetic changes, are also associated with aging. Similar changes occur at the cellular level in a process called senescence, which limits the growth of aging or damaged cells, acting like a natural defense against the formation of tumors. However, cancer cells can find ways to escape this mechanism. Chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) are common types of blood cancers, typically diagnosed around the age of 68. Their occurrence is rare in younger individuals but increases with age. This highlights the need to investigate how aging processes may contribute to these types of cancers. By understanding these mechanisms, we can identify new targets for treatment and prevention.
Our research project has identified specific marks associated with aging in patients with these blood cancers, suggesting that these marks may be linked to how the cancer cells develop. Moreover, this information has helped us discover potential biomarkers, which, if validated in further studies, could be associated with how well a therapy works. Importantly, this therapy has properties that target senescent cells more effectively than regular chemotherapy, potentially leading to fewer side effects. The findings from our project connect the dots between cancer genetics, the aging process, senescence, and the development of blood cancers.
Our research project has identified specific marks associated with aging in patients with these blood cancers, suggesting that these marks may be linked to how the cancer cells develop. Moreover, this information has helped us discover potential biomarkers, which, if validated in further studies, could be associated with how well a therapy works. Importantly, this therapy has properties that target senescent cells more effectively than regular chemotherapy, potentially leading to fewer side effects. The findings from our project connect the dots between cancer genetics, the aging process, senescence, and the development of blood cancers.
This project encompassed a range of both scientific and non-scientific activities divided in 6 work packages (WP) the first three were delved to explore three scientific aims and the fourth to sixth to focus on dissemination and exploitation, training and project managing.
Work Package 1: Aim 1
This package aimed to investigate the methylation profiles of different cell types, focusing on senescence-related changes in healthy and leukemic cells. Despite encountering some challenges, such as limited sample sizes and variations, notable progress was made. Particularly, the study identified key methylation patterns related to a signaling pathway, shedding light on potential connections between aging, senescence, and leukemia. Further analysis of specific genes provided insights into their roles in cell regulation and potential implications for leukemia prognosis and treatment response.
Work Package 2: Aim 2
This package aimed to assess the impact of senolytic drugs on senescent cells in bone marrow, focusing on their effects on hematopoietic stem cells (HSCs) and leukemia cells. While facing challenges in sample acquisition and size, initial observations indicated a reduction in senescent cells following senolytic drug treatment compared to chemotherapy. Functional assays, including Colony Forming Unit (CFU) assays, were developed to evaluate stemness and differentiation capacity. These efforts were complemented by methylation studies aimed at identifying potential biomarkers for treatment response.
Work Package 3: Aim 3
Although this package was not pursued due to resource limitations and strategic decisions, it aimed to explore the methylation changes in senescent and non-senescent HSCs in leukemia mouse models and assess the efficacy of senolytic drugs in preventing disease progression.
Work Package 4: Dissemination and Exploitation:
This package focused on disseminating project findings through various channels, including 2 scientific publications, 1 Organisation of a Conference, 6 Social Media, 3 Mentions on Websites, 7 Participation to a Conference, 3 Participation to an Event other than a Conference or a Workshop and 3 activities were organised jointly with other EU project(s).
Work Package 5: Training:
This package aimed to enhance the researcher's skill set through training courses, scientific meetings, and workshops. I gained proficiency in various scientific techniques and bioinformatics tools, contributing to the successful execution of project tasks. Attendance at scientific meetings facilitated knowledge exchange and networking opportunities crucial for career development.
Work Package 6: Management:
This package focused on project management, ensuring effective coordination of scientific and financial aspects. Regular meetings with supervisors and project managers facilitated communication and decision-making, while collaborations with other institutions contributed to the organization of scientific events and adherence to project guidelines. Compliance with data management requirements demonstrated a commitment to transparent and accountable research practices.
Work Package 1: Aim 1
This package aimed to investigate the methylation profiles of different cell types, focusing on senescence-related changes in healthy and leukemic cells. Despite encountering some challenges, such as limited sample sizes and variations, notable progress was made. Particularly, the study identified key methylation patterns related to a signaling pathway, shedding light on potential connections between aging, senescence, and leukemia. Further analysis of specific genes provided insights into their roles in cell regulation and potential implications for leukemia prognosis and treatment response.
Work Package 2: Aim 2
This package aimed to assess the impact of senolytic drugs on senescent cells in bone marrow, focusing on their effects on hematopoietic stem cells (HSCs) and leukemia cells. While facing challenges in sample acquisition and size, initial observations indicated a reduction in senescent cells following senolytic drug treatment compared to chemotherapy. Functional assays, including Colony Forming Unit (CFU) assays, were developed to evaluate stemness and differentiation capacity. These efforts were complemented by methylation studies aimed at identifying potential biomarkers for treatment response.
Work Package 3: Aim 3
Although this package was not pursued due to resource limitations and strategic decisions, it aimed to explore the methylation changes in senescent and non-senescent HSCs in leukemia mouse models and assess the efficacy of senolytic drugs in preventing disease progression.
Work Package 4: Dissemination and Exploitation:
This package focused on disseminating project findings through various channels, including 2 scientific publications, 1 Organisation of a Conference, 6 Social Media, 3 Mentions on Websites, 7 Participation to a Conference, 3 Participation to an Event other than a Conference or a Workshop and 3 activities were organised jointly with other EU project(s).
Work Package 5: Training:
This package aimed to enhance the researcher's skill set through training courses, scientific meetings, and workshops. I gained proficiency in various scientific techniques and bioinformatics tools, contributing to the successful execution of project tasks. Attendance at scientific meetings facilitated knowledge exchange and networking opportunities crucial for career development.
Work Package 6: Management:
This package focused on project management, ensuring effective coordination of scientific and financial aspects. Regular meetings with supervisors and project managers facilitated communication and decision-making, while collaborations with other institutions contributed to the organization of scientific events and adherence to project guidelines. Compliance with data management requirements demonstrated a commitment to transparent and accountable research practices.
The present results described above have enhanced our understanding of some process required for leukemogenesis, although until results are further validated and additional research is conducted, we could only speculate on the socioeconomic impact. This project not only will impact the leukemogenesis of AML and CLL but also other hematological diseases associated with aging. In the long run, these research results could impact the well-being of a significant portion of the population and the economic stability of national and international health systems, given that the aging population utilizes a majority of health resources. It could also contribute to generating wealth by discovering new targetable molecules for controlling leukemogenesis and bone marrow aging. In addition to the direct impact of the research, this action has also had a great impact on the maturity and training of the fellow, as well as the awareness and illustration of the general public of this topic and the importance of research to stablish Europe in the forefront of well-being and innovation.