Highlight Publication August 2010

Ramadani F, Bolland D, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE, Okkenhaug K (2010)
The PI3K isoforms p110α and p110δ are essential for pre-B cell receptor signaling and B cell development.
Science Signaling 3 ra60
http://dx.doi.org/10.1126/scisignal.2001104

Lay description

Research  into how white blood cells known as B cells develop, has revealed that genes from the Phosphatidylinositol 3-kinase (PI3Ks) family of enzymes are critical in enabling the B cells to produce antibodies in the spleen and lymph nodes. PI3Ks are involved in a diverse range of activities inside cells, generating signalling molecules to control cell growth, proliferation, motility, survival and intracellular trafficking. Faults in these processes can lead to the development of cancer; consequently the PI3Ks are currently among the most hotly pursued drug targets in the pharmaceutical industry.

The PI3K enzymes are made up of two parts, a regulatory subunit and a catalytic subunit known as p110, of which there are four types (isoforms) - p110α, p110β, p110γ and p110δ. Mutations in p110α are seen in many cancers, including breast and colon cancer, and drugs inhibiting the activity of all four of these isoforms are being trialled as anti-cancer drugs. The research now published in the journal Science Signaling is the first description of p110α in immune cells. The findings suggest that drugs targetting p110α specifically may retain significant anti-cancer effect without compromising immunity.

B cells start to develop in the bone marrow, before they mature and populate the spleen and lymph nodes, where they make antibodies to eliminate viruses and bacteria from the body. Previous studies suggested a non-essential role for the PI3K family in early B cell development. However, the new research has shown that if both p110α and p110δ are inhibited, no B cells develop. The spleen and lymph nodes of mice lacking both p110α and p110δ genes were devoid of B cells and virtually no antibodies could be found in the blood. Hence, blocking these enzymes together would have a dramatic effect on the immune system.

The p110γ and p110δ isoforms are produced in cells of the immune system but are not found in other organs and tissues. They are therefore potential therapeutic targets for autoimmune diseases and inflammation. However, it was previously unclear whether p110α was also important in immune cells.

Blocking p110α alone had no effect on B cells, nor did the inhibition of p110β or p110γ. However, if p110δ was blocked, B cells continued to develop but made fewer antibodies, thus potentially dampening unwanted immune responses. It is possible to develop drugs that will inhibit one of these isoforms selectively. For instance, p110α, but none of the other three isoforms, is frequently mutated and hyper-active in tumour cells and is therefore an obvious target in cancer therapy. Although drugs that target p110δ selectively could be useful to treat autoimmune and inflammatory diseases, anti-cancer drugs might be less toxic to the immune system if they are designed to inhibit p110α, but not p110δ. However, as pointed out in a perspective on the article, inhibition of both p110 α and p110δ may be required to treat B cell malignancies.

Press release relating to this publication

About the lead author

Faruk Ramadani is from Kosovo. After obtaining his BSc in Immunology from King’s College London in 2004, he joined the lab of Klaus Okkenhaug as a PhD student. The work of his PhD focused on the role of class IA catalytic PI3K isoforms in lymphocyte development and function. He obtained his PhD in 2009, and has now joined the laboratory of Professor Hannah Gould, King’s College London, working on signal transduction by IgE receptors.