vukAn enzyme that modifies histones is a vital checkpoint on the journey to B cell maturation, according to a new study from scientists at the Monash Biomedicine Discovery Institute, Australia.

The histone modifying enzyme DOT1L, the study reported, is an essential requirement for B cell development in the bone marrow. The study also provided evidence that DOT1L helps immature B cells localize to germinal centers in lymphoid organs—lymph nodes or spleen—where they multiply and alter their antibody genes to bind to pathogen molecules with high affinity, thereby mounting a successful immune response.

Histone modification, a form of epigenetic regulation, is essential for the ability of immune cells to reprogram their gene expression during maturation. The maturation of B cells, immune cells responsible for adaptive humoral immunity, is crucial for the clearance of pathogens.

Earlier studies on DOT1L have focused on its role in inducing cancer-promoting gene expression in some B cell leukemias. Yet, despite its obvious importance, the role of DOT1L in B lymphocyte biology had not been investigated until now.

“There are a number of drugs in early clinical trials to target DOT1L for acute lymphoblastic leukemia, but there is little known about how turning DOT1L off would affect the ability of B cells to form antibodies,” said Kim L. Good-Jacobson, associate professor at the department of biochemistry and molecular biology, Monash University.

This study describing the effects of selectively removing the expression of DOT1L from developing B lymphocytes in mice is reported in the article, “The Histone Methyltransferase DOT1L is Essential for Humoral Immune Responses,” which was published in the journal Cell Reports.

Mice with DOT1L deficient B cells show a depletion of developing B cells in the bone marrow although the numbers of precursor B cells that originate before the expression of DOT1L is turned off in the lineage, are not affected.

Understanding how B cells are regulated during the early part of the immune response is critical from a fundamental biological perspective, said Good-Jacobson. Compromised development of B cells in the bone marrow culminates in a reduction of mature B cells in the peripheral lymphoid organs—the lymph nodes and the spleen.

A concurrent study from the lab next door to Good-Jacobson headed by Colby Zaph, also published in the same issue of Cell Reports, focused on the role of DOT1L in controlling how T cells, white blood cells critical for immunity to infections, make the choice to develop into distinct subsets.

Good-Jacobson and her colleagues had earlier established the expression of DOT1L in a few subtypes of B cells. “That finding, combined with early work that Colby had done into the specific role of T cells, gave us the impetus to investigate whether it was essential for B cells,” she said.

The generation of antibodies by B lymphocytes is critical for protecting us against viral infections and underpins the efficacy of most vaccines. In addition to secreting antibodies to help clear infections, B cells are immune memory cells that respond rapidly with an even larger army of antibodies, upon reinfection.

“What we found was that if B cells didn’t have DOT1L they were able to be turned on by infection, but the engine would sputter out, they’d get to a certain point in forming an antibody response but couldn’t go any further—they are completely shut down before productive antibody and immune memory can be formed,” said Good-Jacobson.

The study revealed that DOT1L is critical to turning on an effective B cell response during infection or in response to immunization. The authors also showed that exposure of DOT1L deficient mice to influenza infection or immunization resulted in fewer antibody-secreting mature B cells and a failure of germinal centers to form in lymphoid organs.

“If you’re going to use a drug that stops DOT1L from functioning it’s really important to know what it’s actually regulating because it’s critical for the body to mount an effective antibody response to infection. You’re going to have problems fighting off infection down the track if you’re using these drugs.” This indicates caution that must be adopted in using this crucial enzyme as a target for the development of therapeutics.

Good-Jacobson and her team are set to investigate the role of DOT1L in driving genes in different B cell-derived cancers.

“Our next step is to look at this molecule in the formation of immunity itself,” she said.

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