Tuesday, May 26, 2015

Leukemia - when RAG genes go Rogue

Receptor diversity of the adaptive immune system (in both B and T cells) is driven by RAG genes. Additionally, B cells also express AID that is responsible for Ig somatic hyper-mutation (SHM) and class switch recombination (CSR). Basically, RAG and AID genes represent naturally occurring gene editing system in mammals.

However, evolution always come at a cost. New paper in Nature Immunology suggests that improperly expressed RAG and AID genes may contribute to the evolution to childhood leukemia.     

By looking at AID expression pattern during human or mouse bone marrow B cell lymphopoiesis, the authors observed that IL-7 signaling played a major role in preventing AID expression prior to small pre-BII cell stage.

In vitro experiments on pre-BII cells from AID-GFP mouse confirmed that withdrawal of IL-7, in combination with LPS (a surrogate for inflammation), induced co-expression of both AID and surface Ig  κ Light-chain (a surrogate marker for RAG gene activity).

Further experiments showed that transduction of mouse pre-BII cells with WT version of pre-leukemic genetic lesion ETV6-RUNX1 induced RAG gene expression.

Finally, adoptive transfer of ETV6-RUNX1 transduced WT pre-BII cells that underwent 5 cycle of in vitro IL-7 withdrawal in combination with LPS, produced leukemia in the NOD.SCID hosts (which lacks its own adaptive immune system). However, ETV6-RUNX1 transduced pre-BII cells from AID-KO or RAG-KO mouse failed to produce leukemia.

In summary, these results indicate that pre-BII cells are vulnerable for improper co-expression of AID and RAG genes due to combination of ETV6-RUNX1 genetic lesion and inflammatory milieu (that may diminish IL-7 signaling). Such condition may arise when the humans are exposed to childhood infections later in their life. It is believed that timely vaccination could reduce incidence of such leukemia in children.     

David Usharauli

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