Acute lymphoblastic leukemia of pre-B cells (pre-B ALL) is the most frequent form of leukemia affecting children in Western countries. Evidence is accumulating that genetic factors play an important role in conferring susceptibility/ resistance to leukemia in children. In this regard, activating killer-cell immunoglobulin-like receptor (KIR) genes are of particular interest. Humans may inherit different numbers of the 6 distinct activating KIR genes. Little is known about the impact of this genetic variation on the innate susceptibility or resistance of humans to the development of B-ALL. We addressed this issue by performing a case-control study in Canadian children of white origin. Our results show that harboring activating KIR genes is associated with reduced risk for developing B-ALL in these children. Of the 6 activating KIR genes, KIR2DS2 was maximally associated with decreased risk for the disease (P ‫؍‬ 1.14 ؋ 10 ؊7 ). Furthermore, our results showed that inheritance of a higher number of activating KIR genes was associated with significant reductions in risk for ALL in children. These results were also consistent across different ALL phenotypes, which included children with pre-T cell ALL. Our study provides novel insights concerning the pathogenesis of childhood leukemia in white children and has implications for the development of new immunotherapies for this cancer. (Blood. 2011;118(5): 1323-1328)

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Activating Killer-cell Immunoglobulin-like Receptor (KIR) genes constitute a subset of KIR family. The genes are expressed as activating receptors on the surface of NK cells as well as on a subset of T cells. The receptors interact with poorly defined ligands and decrease the activation threshold of these cells. Overall, they increase immune reactivity of the individuals. The activating KIR genes, like other KIR genes, are highly polymorphic. Furthermore, KIR haplotypes differ from each other with respect to the number of activating genes. Some haplotypes have no activating genes while others may carry upto seven such genes. Consequently, humans differ from each other with respect to the number of inherited activating KIR genes. Activating KIR genes have been associated with autoimmune diseases. However, little is known about their association with Crohn’s Disease. We have investigated the potential association of these genes with this disease in Canadian children of the French origin. Our results show that these genes act as risk factors for developing CD in these children. An increased number of inherited activating KIR genes correspondingly increased the risk for the disease. These results were also replicated in the Canadian (Caucasian) children of non-French origin. Collectively, our results suggest that activating KIR genes act as risk factors in developing CD in humans. The study was supported by the Crohn’s and Colitis Foundation of Canada (CCFC)