Ikaros proteins drive pre-B cell differentiation
In the classic Super Mario Bros video games, you had to collect a certain number of gold stars to advance between levels. Life as a burgeoning B cell is much the same. B cell development occurs in several stages, and new research from the CSC has revealed that the ‘currency’ that determines progress between stages is the dosage of Ikaros DNA binding proteins.
Key to the healthy functioning of our immune system, mature B lymphocytes specialise in making antibodies. And Ikaros – a family of transcription factors that regulates gene expression – is central to their development. New research published in Blood, reveals its importance. “If you look at the expression of Ikaros transcription factors during B cell development, you see upregulation,” says Matthias Merkenschlager (Lymphocyte Development Group). “We designed a system to control the amount of Ikaros in the cell nucleus. Measuring gene expression before and after inducing Ikaros allows us to see which genes are affected.”
They mapped the binding sites of Ikaros throughout the genome and combined this information with the gene expression data to draw up a list of Ikaros target genes. “We know that certain pathways, such as signalling through B cell receptors and cell cycle pathways, are important to B cell development,” says Merkenschlager. “With the list, we can assess which players in the pathway are regulated by Ikaros.” The correlation between Ikaros-regulated genes and players in these pathways paints a clear picture: there is almost no aspect of the process that is not affected by Ikaros. “By mapping Ikaros target genes onto these pathways, we showed that the influence of these transcription factors is pervasive,” says Merkenschlager.
As B cells advance along the stepping-stones of the differentiation path, one crucial transition is from ‘cycling’ to ‘resting’ B cell progenitors. Cycling B cells are a dangerous group: with unlimited capacity for self-renewal, they are one misstep from developing into leukaemia. Harnessing the power of an available database of gene expression along the differentiation pathway, the researchers investigated precisely when Ikaros was acting. “This highlighted two important transitions,” says Merkenschlager. “The first is making a B cell initially from lymphoid progenitor cells. The second is between cycling and resting B cell progenitors. Our experiments show that the dosage of Ikaros determines the progression from the cycling to the resting stage of B cell progenitor differentiation. Ikaros dosage defines where the cells are on the pathway.”
If Ikaros governs the transition out of the cycling phase, could it hold the cure to B cell leukaemias? Identifying how Ikaros acts may shine a light on new targets for therapy. But before that, there is much more to ask. One target that has emerged from this and other studies is Myc – a well-known oncogene. Now the team hopes to uncouple Myc from Ikaros to unveil the next piece of the lymphocyte development puzzle.
Reference:Ferreirós Vidal, I., Carroll, T., Taylor, B., Terry, A., Liang, Z., Bruno, L., Dharmalingam, G., Khadayate, S., Cobb, B. S., Smale, S. T., Spivakov, M., Srivastava, P., Petretto, E., Fisher, A. G., Merkenschlager, M., Jan. 2013. Genome-wide identification of ikaros targets elucidates its contribution to mouse b cell lineage specification and pre-B cell differentiation. Blood. Abstract
Super Mario Bros is a trademark of Nintendo. Image credit Jelene Morris (CC-BY 2.0)