SirT-IMLEU · Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis

Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis

Yearly, roughly 53.000 people worldwide are diagnosed with acute lymphoblastic leukemia (ALL), a type of cancer characterized by the development of large numbers of immature lymphocytes. ALL originated from B cell precursors (B-ALL) is the most common pediatric cancer. This MSCA Action, entitled “Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis”, aimed to identify novel molecular mechanisms required for the development of immunity and to further understand how their deregulation participates in the formation of acute lymphoblastic leukemia of B-ALL. Specifically, the functional relationship between Sirtuins (a family of proteins critical for the function of the genome) and the master regulator PAX5 (key transcription factor required to produce B lymphocytes) have been studied. The main goal of the project was to define the role of SIRT7 in B cell development and leukemia. Our main hypothesis was that SIRT7-dependent regulation of PAX5 played a fundamental role in B cell development and that this interaction was required to sustain B cell fate. A multidisciplinary state-of-the-art approach was designed, including molecular and cellular biology, genomics and mouse models to unravel the molecular mechanisms of SIRT7 in immune regulation. Three different specific aims were defined: 1: Characterization of the functional relationship between SIRT7 and PAX5 in leukemic cells. 2: To analyze the interplay of PAX5 and SIRT7 in gene transcriptional regulation. 3: To determine the contribution of SIRT7 in the maintenance of B cell identity and leukemogenesis. This project has provided significant advances in our understanding of the molecular biology of B-ALL, identifying a new regulator of B cell development, SIRT7, and defining for the first time mechanisms of PAX5 protein stabilization, thus opening new paths for therapeutic interventions. SIRT7 activating compounds could serve as a novel strategy to restore PAX5 protein levels and reduce tumor progression. This action represents the first attempt to perform such approach. Furthermore, a novel role of SIRT7 in B lymphocyte differentiation has been uncovered, shedding shed light into novel regulatory mechanisms of PAX5 activity, with major implications for treatments for leukemia patients.

Data: CORDIS, © European Union