Ricerc@Sapienza

Multiple myeloma (MM) is a hematologic cancer characterized by the clonal expansion of malignant plasma cells (PCs) in the bone marrow microenvironment. Progression of MM is supported also by the impairment of the immune response. Natural Killer (NK) cells are innate lymphocytes that represent a first line of defense against tumor growth and metastasis spreading. Several studies have shown that NK cells participate to the surveillance of MM thanks to their ability to directly kill cancer cells expressing several NK cell activating ligands. On the other hand, cancer cells can release a plethora of soluble factors able to modulate NK cell-mediated functions. Activation of DNA Damage response (DDR) by genotoxic agents can induce NK cell activating ligands on the tumor cell surface and at the same time trigger type I interferon production. Increasing evidence has demonstrated that coordinated synthesis and degradation of dNTPs is critical for numerous cellular processes, such as fidelity of DNA synthesis and DNA damage repair. In this regard, Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a deoxyribonucleotide triphosphate (dNTP) triphosphohydrolase and a nuclease that regulates the intracellular dNTP pool. Althought SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections, emerging evidence show that mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi-Goutières syndrome. The involvement of SAMHD1 in the response to DNA damage in cancer cells has been also described. In this project we will investigate: i) the role of SAMHD1 in the DDR induced by genotoxic agents in multiple myeloma cells; ii) the involvement of SAMHD1 in the upregulation of NK cell activating ligands as well as type I interferons in response to genotoxic stress.