Mechanisms of Sirtuin-dependent regulation of immunity and leukemogenesis

ended

Acute lymphoblastic leukemia, the most common pediatric cancer, originates in many cases from the malignant transformation of a developing Blymphocyte in the bone marrow. Understanding the mechanisms of B cell maturation and how their perturbation contributes to the onset of this pathology is essential for evolving improved strategies for those patients not responding to current therapies. Importantly, this project aims to discover novel mechanisms of B lymphopoiesis by studying the interplay between SIRT7, a Sirtuin family member critical for genome homeostasis, and PAX5, a transcription factor required for B cell development and to sustain B cell identity. Sirtuins play key roles in the maintenance of genome integrity under stress and their deficiency has been linked to the pathogenesis of cancer. Importantly, SIRT7 is highly expressed in developing lymphocytes yet their role in immune cells and its relationship with leukemia awaits further investigation. With this project, we will define SIRT7-dependent regulatory mechanisms of PAX5 protein turnover, its relationship with PAX5-associated transcriptional programs and how their functional interplay is abnormal in leukemic cells. Because PAX5 is found in haploinsufficiency in most of the cases of acute lymphoblastic leukemia of B-cell progenitors, the development of this project is highly significant to the society as it has the potential to generate novel approaches to restore PAX5 protein levels, with important implications for clinical interventions and the cure of this disease.