My project Chromatin Regulation Of Normal And Malignant Haematopoiesis (ChRONAM-H) proposed a multidisciplinary framework to explore the functions of Chromatin Factors (CFs) during hematopoietic lineage commitment and malignant transformation.
Here is a summary of the main results achieved during this project:
First I have developed a methodology to interrogate the lineage specifying roles of Chromatin Factors (CFs) in hematopoiesis. This methodology relies on differentiation systems where cells are pushed into specific lineages using precise growth conditions and CRISPR is used to disrupt specific CFs in a high-throughput manner. This permits a large-scale interrogation of the relevance of different factors in the development of specific hematopoietic lineages. Using this methodology I have characterized the roles of 680 Chromatin Factors during hematopoiesis identifying 200 CFs as key lineage regulators; this represents the first comprehensive study of Chromatin Factors in a developmental process.
Next, I have used state-of-the-art genome profiling methods to study how key Chromatin Factors regulate the different hematopoietic lineages (progenitors, erythroid and myeloid) and how they operate in an abnormal leukemic setup. This has enabled me to dissect gene regulatory programs controlled by these CFs and to highlight the interactions between Transcription and Chromatin Factors that are key for cellular identities. Of note, I have identified two interactions with an applied potential in leukemia (Brd9-Cebp and Smarcb1-Stat5a)
Then, using single-cell technologies I have characterized in depth the cellular and molecular mechanisms regulated by Chromatin Factors during hematopoiesis and identify differential behaviors in leukemia. Key findings are an unexpected functional diversity for Chromatin Factors with activation roles, a common behavior for repressive factors as attenuators of excessive inflammatory responses - which can be exploited to treat inflammation-related diseases like lupus. And, the identification of chromatin factors that permit unlimited growth of leukemic cells that represent potential targets for treatment via small-molecule inhibition, highlighting this approach as an excellent tool for drug discovery.
In summary, I have generated a roadmap CFs roles in hematopoiesis and leukemia highlighting therapeutic targets.
The findings described above have been presented at three international conferences in 2022. In addition, a research article presenting this work is currently under revision in Nature Genetics and has received a very favorable reception and I expect this article to be published during the first trimester of 2023, which will be made available to the general public by following the Gold Open Access route.
Finally, we have identified several avenues to exploit the results obtained in this project. First, we have established partnerships with researchers from the University of Navarre Clinic to validate the translational potential of our findings in human leukaemias. Second, we have established a partnership with Relation Therapeutics (London), a start-up company applying machine learning to discover novel therapeutic targets. In both initiatives, we have protected the Intellectual Property (IP) of the findings.
