Report from the Killer-cell Immunoglobulin-like Receptors (KIR) component of the 17th International HLA and Immunogenetics Workshop.

The goals of the KIR component of the 17th International HLA and Immunogenetics Workshop (IHIW) were to encourage and educate researchers to begin analyzing KIR at allelic resolution, and to survey the nature and extent of KIR allelic diversity across human populations. To represent worldwide diversity, we analyzed 1269 individuals from ten populations, focusing on the most polymorphic KIR genes, which express receptors having three immunoglobulin (Ig)-like domains (KIR3DL1/S1, KIR3DL2 and KIR3DL3). We identified 13 novel alleles of KIR3DL1/S1, 13 of KIR3DL2 and 18 of KIR3DL3. Previously identified alleles, corresponding to 33 alleles of KIR3DL1/S1, 38 of KIR3DL2, and 43 of KIR3DL3, represented over 90% of the observed allele frequencies for these genes. In total we observed 37 KIR3DL1/S1 allotypes, 40 for KIR3DL2 and 44 for KIR3DL3. As KIR allotype diversity can affect NK cell function, this demonstrates potential for high functional diversity worldwide. Allelic variation further diversifies KIR haplotypes. We determined KIR3DL3 ∼ KIR3DL1/S1 ∼ KIR3DL2 haplotypes from five of the studied populations, and observed multiple population-specific haplotypes in each. This included 234 distinct haplotypes in European Americans, 191 in Ugandans, 35 in Papuans, 95 in Egyptians and 86 in Spanish populations. For another 35 populations, encompassing 642,105 individuals we focused on KIR3DL2 and identified another 375 novel alleles, with approximately half of them observed in more than one individual. The KIR allelic level data gathered from this project represents the most comprehensive summary of global KIR allelic diversity to date, and continued analysis will improve understanding of KIR allelic polymorphism in global populations. Further, the wealth of new data gathered in the course of this workshop component highlights the value of collaborative, community-based efforts in immunogenetics research, exemplified by the IHIW.

IFNG +874 A/T is associated with acute lymphoblastic leukemia in Mexican Mestizos.

Acute lymphoblastic leukemia (ALL), the most common type of cancer in children worldwide, has one of the highest incidence rates in Mexico. It is a multifactorial disease and different cytokine single nucleotide polymorphisms (SNP), have been associated with ALL expression. Few studies have been published analyzing IFNG +874 T/A and IL2 -330 G/T in this type of leukemia. These SNPs are involved in high or low expression, and are central to cellular immunity, influencing greatly tumor growth. The purpose of this work was to explore the association of IFNG +874 A/T (rs2430561) and IL2 -330 G/T (rs2069762) SNPs with ALL susceptibility and/or protection in 488 Mexican Mestizos patients, as compared to 950 Mexican Mestizo healthy controls. The results demonstrated that IFNG +874 T allele (pc = 0.00004, OR = 0.673) and the TT genotype (pc = 0.00015, OR = 0.349), protect against ALL expression with no specific gender association; however, the TT homozygote genotype (vs. TA+AA) seems more protective in males (pc = 0.00683). IL2 -330 G/T does not contribute to the development of ALL. In healthy Mexicans, the most common genotypes for IL2 and IFNG, are the low cytokine producers, suggesting that the genetic background in this ethnic group, may be partly responsible for the high incidence of ALL. These results show for the first time in Mexicans, the relevant role that IFNG SNP has in the genetic etiology of ALL. Thus, a large group of patients belonging to different ethnicities will be very helpful to study in order to demonstrate if these SNPs contribute to the genetic etiology of ALL, as shown here in Mexican Mestizos.

Expression profile of NF-κB regulated genes in sporadic colorectal cancer patients.

Colorectal cancer (CRC) is the fourth leading worldwide cause of cancer-associated mortalities. Nuclear factor-κB (NF-κB) is a transcriptional regulator of multiple genes associated with CRC. Tumor tissue were compared with normal adjacent mucosa from 30 sporadic patients with CRC were investigated. A total of 8 non-CRC patients were analyzed as a control group. In the present study, the protein expression of NF-κB/p65 was detected by immunohistochemistry, and the gene expression profiles of cyclin D1 (CCND1), prostaglandin-endoperoxide synthase 2, vascular endothelial growth factor A, matrix metallopeptidase 9, BCL2 apoptosis regulator (BCL2), BCL2 like 1, nitric oxide synthase 2, tumor necrosis factor and arachidonate lipoxygenase were detected by reverse transcription-quantitative polymerase chain reaction. NF-κB/p65 and genes expression profiles were classified according to tumor-node-metastasis (TNM) clinicopathological parameters, followed by statistical analysis. Higher protein expression of NF-κB/p65 in the cytoplasm of tumor tissues compared with adjacent normal mucosa was reported; this increment was positively associated with all clinicopathological parameters, except for tumor localization site. The selected genes demonstrated a diverse associative pattern when analyzed with clinicopathological parameters. CCND1 was positively associated with all TNM parameters and BCL2 was negatively associated with all TNM parameters, thus indicating their importance as strong molecular biomarkers for CRC. According to these results, not all selected genes regulated by NF-κB/p65 show increased expression during CRC development, whereas the transcription factor did. The present study suggests that NF-κB/p65 overexpression is necessary for CRC establishment and progression, but its transcriptional activity is not sufficient to regulate all target genes in CRC. NF-κB/p65 and the gene expression profiles reported in the present study may be therapeutically useful. Considering the heterogeneity of the disease, the particular evaluation of these molecules may allow for the selection of proper diagnosis, treatment and follow-up for patients with sporadic CRC.

Curcumin potentiates the effect of chemotherapy against acute lymphoblastic leukemia cells via downregulation of NF-κB.

Acute lymphoblastic leukemia (ALL) accounts for 30% of all pediatric cancers. Currently available treatments exhibit toxicity and certain patients may develop resistance. Thus, less toxic and chemoresistance-reversal agents are required. In the present study, the potential effect of curcumin, a component of Curcuma longa, as a pharmacological co-adjuvant of several chemotherapeutic agents against ALL, including prednisone, 6-mercaptopurine, dexamethasone, cyclophosphamide, l-asparaginase, vincristine, daunorubicin, doxorubicin, methotrexate and cytarabine, was investigated in the REH ALL cell line cultures treated in combination with chemotherapeutic agents and curcumin. The results of cell viability, gene expression and activation of NF-κB and caspase 3 indicated that curcumin potentiates the anticancer effects of the aforementioned chemotherapeutic agents in the REH ALL cell line. Following treatment with the above chemotherapeutic agents, curcumin enhanced caspase-3 activation and downregulated nuclear factor-kappa B (NF-κB) activation. Curcumin also downregulated the oxidative stress induced by certain chemotherapies. Notably, curcumin did not affect the gene expression of cell survival proteins such as B-cell lymphoma (Bcl)-2, Bcl-extra large, survivin, c-Myc and cyclin D1, which are regulated by the NF-κB transcription factor. In conclusion, curcumin has the potential to improve the effect of chemotherapeutic agents against ALL.