Discovering Mechanisms Behind B-Lymphocyte Maturation

Researchers from the Chromatin Biology lab at the Josep Carreras Leukaemia Research Institute just discovered a fundamental mechanism controlling B-lymphocyte maturation in the bone marrow. Defects in this process lead to B-cell Acute Lymphoblastic Leukaemia, the most common childhood blood cancer. This new knowledge may open the door to developing new drugs targeting the B-cell maturation main players, such as the protein SIRT7, of the sirtuin family.

Over four hundred people, 80% of them being children under 14 years old, will be diagnosed with B-cell Acute Lymphoblastic Leukaemia (B-ALL) next year in Spain, according to the latest projections from the Spanish network of cancer registries (REDECAN). Survival rates for this rapid-growing and aggressive type of blood cancer are high in youth, but fall rapidly with age, especially after 40, stressing the need for new therapeutic alternatives.

B-ALL arises when B-lymphocytes - the antibody producing cells of the immune system - fail to properly mature in the bone marrow, leading to the accumulation of immature progenitors and affecting the whole production of blood cells. This causes severe symptoms, like anaemia, generalised weakness and immune failure. While current therapeutic options include chemotherapy and immunotherapy, this study opens new avenues for novel approaches aiming at restoring normal B cell maturation.

The prestigious journal Nature Immunology publishes the latest work of the Chromatin Biology lab, led by Dr. Alejandro Vaquero at the Josep Carreras Institute, in which researchers describe a molecular mechanism controlling the transcription factor PAX5, the key regulator of B-cell maturation and a well-documented target for B-ALL. To this end, the team, spearheaded by Andrés Gámez and co-supervised by Dr. Berta Vázquez, teamed-up with other researchers at the Josep Carreras Institute, such as Dr. Manel Esteller and Dr. Jose Luis Sardina, as well as from other institutions in Spain and abroad.

PAX5 regulates B-cell identity by controlling the activation of its genetic program, guiding B-cell progenitors through the maturation process. According to the research, this is an exceptionally subtle process in which PAX5 is sequentially stabilised and de-stabilised through a chemical modification known as acetylation. Two proteins are in charge of these chemical modifications: the deacetylase SIRT7 on one side, removing the modification, and the acetyltransferase PCAF on the other, adding it to PAX5.

SIRT7, from the sirtuin family, has been extensively studied in the last years by Dr. Vaquero’s group in collaboration with well-recognized experts from around the world (Sweden, USA, and Germany) and the results show that it is a very important protein during B-cell development, among other important cellular processes. In the current research, SIRT7 deacetylase activity enhances PAX5 stability within the cell, allowing its activity for longer times. In fact, the expression profile of SIRT7 increases during B-cell maturation in vivo, and closely correlates with PAX5 expression levels. Conversely, absence of SIRT7 in mice blocks B-cell differentiation in the bone marrow, producing immunodeficiency.

Mutations inactivating one copy of the PAX5 gene -we humans have two copies of each gene- are found in 30% of B-ALL cases. It turns out our cells need the two copies working to produce enough PAX5, so these monoallelic mutations count as an important driver of leukemogenesis. Furthermore, increasing PAX5 protein levels in B-ALL cells is known to induce leukemic cell death. Thanks to the new understanding of the PAX5 delicate balance, and to the ability of SIRT7 to control it, the research team suggests a possible new therapeutic approach aiming at reinforcing SIRT7 activity in B-ALL patients to keep PAX5 levels higher within leukemic cells.

Fundamental research on clinical challenges has the potential to broaden our view of diseases like B-ALL and other related illnesses, like B-cell chronic leukaemia and T-cell leukaemia, and deeper understandings open the door to innovative approaches, that can make a difference for blood cancer patients in the future.

Reference: Gamez-Garcia A, Espinosa-Alcantud M, Bueno-Costa A, et al. A SIRT7-dependent acetylation switch regulates early B cell differentiation and lineage commitment through Pax5. Nat Immunol. 2024. doi: 10.1038/s41590-024-01995-7

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