PROJECT
SUPERVISORS

Project Supervisor

Raffaella di Micco

Background

The molecular mechanisms of stress responses in stem cells have always been my main area of interest and fascination. During my PhD training, I investigated the molecular mechanisms by which activated oncogenes induce DNA damage and cellular senescence. After graduation, I focused on the study of alterations of chromatin structure during senescence and discovered that heterochromatin formation induced by oncogenes is the consequence of DNA replication stress in the cells.

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In 2010, I moved to United States for postdoctoral training in the laboratory of Dr. Eva Hernando at NYU School of Medicine to understand the epigenetic and transcriptional regulation in stem cells. By using genetic and chemical-based approaches, I identified novel molecular mechanisms involved in stem cell maintenance, with a particular focus on the epigenetic and transcriptional regulator BRD4. I established my independent research team at the San Raffaele-Telethon Institute for Gene Therapy in Milan in early 2016.

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Research

The research in my lab fully capitalizes on my scientific expertise in DNA damage, genome integrity, senescence, epigenetics, and disease and involves, as a model system, the human hematopoietic stem and progenitor cells (HSPCs). In particular, as a team, we seek to dissect the cellular responses to stress in hematopoietic cells (e.g. hematopoietic stem cells and T cells) upon genetic engineering and in hematological conditions associated with premature exhaustion and DNA repair defects including bone marrow failure syndromes.

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We employ quantitative imaging, cutting-edge genomic technologies and take advantage of uniquely available gene editing platforms and primary samples to identify the molecular determinants that promote dysfunction in human HSPCs under stress. Our long-term goal is to successfully engineer human hematopoiesis for disease modeling and to design innovative hypothesis-driven strategies for more effective, safer and clinically broader gene therapy applications.

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Publications

Gambacorta V, Beretta S, Ciccimarra M, Zito L, Giannetti K., Andrisani A., Gnani D., Zanotti L., Oliveira G, Carrabba M, Cittaro D, Merelli I, Ciceri F., Di Micco R§, Vago L §. (2022) Integrated Multiomic Profiling Identifies the Epigenetic Regulator PRC2 as a Therapeutic Target to Counteract Leukemia Immune Escape and Relapse. Cancer Discovery. 2022 Jun 2;12(6):1449-1461. doi:10.1158/2159-8290.CD-21-0980. §corresponding author.

Biavasco R, Lettera E, Giannetti K, Gilioli D, Beretta S, Conti A, Scala S, Cesana D, Gallina P, Norelli M., Basso-Ricci L., Bondanza, Cavalli G, Ponzoni M, Dagna L, Doglioni C, Aiuti A, Merelli I, Di Micco R§, Montini E. (2021) Oncogene-induced senescence in hematopoietic progenitors features myeloid restricted hematopoiesis, chronic inflammation, and histiocytosis. Nature Communications. Jul 27;12(1):4559. doi: 10.1038/s41467-021-24876-1. §corresponding author.

Di Micco R. §, Krizhanovsky V. Baker D. and d’Adda di Fagagna§. Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021). 2021 Feb;22(2):75-95. doi: 10.1038/s41580-020-00314-w. Epub 2020 Dec 16.Nature Reviews Molecular and Cellular Biology (Special Issue on Aging). § corresponding author

Schiroli G.* Conti A.*, Ferrari S, della Volpe L, Jacob A, Albano L, Beretta S, Calabria A, Vavassari V, Gasparini P, Salataj E, Ndiaje-Lobry D, Brombin C, Chaumeil J,Montini E, Merelli I, Genovese P, Naldini L. and Di Micco R.&. Precise Gene Editing Preserves Hematopoietic Stem Cell Function Following Transient p53-Mediated DNA Damage Response.(2019) Cell Stem Cell. Apr 4;24(4):551-565.e8. doi: 10.1016/j.stem.2019.02.019. Epub 2019 Mar 21. & last and corresponding author.

Gnani D, Crippa S, Della Volpe L, Rossella V, Conti A, Lettera E, Rivis S, Ometti M, Fraschini G, Bernardo ME,, Di Micco R.§. An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program. Aging Cell. 2019. Jun;18(3):e12933. doi: 10.1111/acel.12933. Epub 2019 Mar 3. § corresponding author