Role of Sirtuins in haematopoiesis and leukaemia

Abstract

[eng] Haematopoiesis is the process by which haematopoietic stem cells replenish all blood cell types, including myeloid cells and lymphocytes, throughout life in mammals. In particular, B lymphocytes or B-cells are the key mediators of humoral immunity by secreting antigen-specific antibodies that identify and neutralise noxious agents. B-cells develop in the bone marrow through sequential differentiation into several progenitor stages that progressively acquire a specialised identity and lose their lineage potential to become committed to the B-cell lineage. This is orchestrated by a number of lineage- specific transcription factors, including PAX5, which controls virtually all aspects of B- lymphopoiesis. Importantly, defects in haematopoietic progenitors can lead to the development of haematological malignancies, such as B-cell acute lymphoblastic leukaemia (B-ALL), the most common cancer in children. In B-ALL, PAX5 is a potent tumour suppressor that is frequently targeted by monoallelic inactivating mutations, and the reconstitution of PAX5 physiological levels is known to induce leukaemic cell death. However, the mechanisms controlling PAX5 protein dynamics are poorly understood, which has prevented its exploitation as a pharmacological target. Haematopoiesis provides a unique model to study the epigenetic basis of cell identity and malignancy. Furthermore, epigenetic regulators are frequently targeted by deleterious mutations in haematological malignancies. One of such regulators are sirtuins, a family of NAD+-dependent deacetylases that coordinate cellular adaptations to stress, play critical functions in organismal physiology and ageing, and have emerged as attractive anti- cancer targets. Surprisingly, while the roles of sirtuins in immunity have been extensively studied, very little is known about their relevance in haematopoietic differentiation and leukaemia, which prompted us to address this gap of knowledge. Here, we identified a molecular mechanism linking the sirtuin family member SIRT7 with B-cell development and malignancy through the regulation of PAX5. We describe that SIRT7 is upregulated in developing B-cells, where it collaborates with PAX5 to transcriptionally repress lineage potential and sustain B-cell development and commitment. SIRT7 imposes a dynamic deacetylation switch on a single PAX5 residue that controls its protein stability and functions. Acetylated PAX5 poorly binds to chromatin and fails to regulate most of its target genes and to drive both development and commitment. In contrast, deacetylated PAX5 stringently controls transcription and ultimately restores B-cell commitment but not differentiation, which depends on the coordinated action of both proteoforms. Importantly, the SIRT7/PAX5 interplay is conserved in B-ALL cell lines and patients, where SIRT7 exerts a strong tumour suppressor function, presumably through this mechanism. Our findings define an important function of SIRT7 in B-cell identity and may provide a rationale to therapeutically target PAX5 in B-ALL.