Human AML activates the aryl hydrocarbon receptor pathway to impair NK cell development and function.

Acute myeloid leukemia (AML) can evade the mouse and human innate immune system by suppressing natural killer (NK) cell development and NK cell function. This is driven in part by the overexpression of microRNA (miR)-29b in the NK cells of AML patients, but how this occurs is unknown. In the current study, we demonstrate that the transcription factor aryl hydrocarbon receptor (AHR) directly regulates miR-29b expression. We show that human AML blasts activate the AHR pathway and induce miR-29b expression in NK cells, thereby impairing NK cell maturation and NK cell function, which can be reversed by treating NK cells with an AHR antagonist. Finally, we show that inhibition of constitutive AHR activation in AML blasts lowers their threshold for apoptosis and decreases their resistance to NK cell cytotoxicity. Together, these results identify the AHR pathway as a molecular mechanism by which AML impairs NK cell development and function. The results lay the groundwork in establishing AHR antagonists as potential therapeutic agents for clinical development in the treatment of AML.

Probing predilection to Crohn's disease and Crohn's disease flares: A crowd-sourced bioinformatics approach.

Background: Crohn's Disease (CD) is an inflammatory disease of the gastrointestinal tract that affects millions of patients. While great strides have been made in treatment, namely in biologic therapy such as anti-TNF drugs, CD remains a significant health burden. Method: We conducted two meta-analyses using our STARGEO platform to tag samples from Gene Expression Omnibus. One analysis compares inactive colonic biopsies from CD patients to colonic biopsies from healthy patients as a control and the other compares colonic biopsies from active CD lesions to inactive lesions. Separate tags were created to tag colonic samples from inflamed biopsies (total of 65 samples) and quiescent tissue in CD patients (total of 39 samples), and healthy tissue from non-CD patients (total of 30 samples). Results from the two meta-analyses were analyzed using Ingenuity Pathway Analysis. Results: For the inactive CD vs healthy tissue analysis, we noted FXR/RXR and LXR/RXR activation, superpathway of citrulline metabolism, and atherosclerosis signaling as top canonical pathways. The top upstream regulators include genes implicated in innate immunity, such as TLR3 and HNRNPA2B1, and sterol regulation through SREBF2. In addition, the sterol regulator SREBF2, lipid metabolism was the top disease network identified in IPA (Fig. 1). Top upregulated genes hold implications in innate immunity (DUOX2, REG1A/1B/3A) and cellular transport and absorption (ABCG5, NPC1L1, FOLH1, and SLC6A14). Top downregulated genes largely held roles in cell adhesion and integrity, including claudin 8, PAQR5, and PRKACB.For the active vs inactive CD analysis, we found immune cell adhesion and diapedesis, hepatic fibrosis/hepatic stellate cell activation, LPS/IL-1 inhibition of RXR function, and atherosclerosis as top canonical pathways. Top upstream regulators included inflammatory mediators LPS, TNF, IL1B, and TGFB1. Top upregulated genes function in the immune response such as IL6, CXCL1, CXCR2, MMP1/7/12, and PTGS2. Downregulated genes dealt with cellular metabolism and transport such as CPO, RBP2, G6PC, PCK1, GSTA1, and MEP1B. Conclusion: Our results build off established and recently described research in the field of CD. We demonstrate the use of our user-friendly platform, STARGEO, in investigating disease and finding therapeutic avenues.

Dissecting novel mechanisms of hepatitis B virus related hepatocellular carcinoma using meta-analysis of public data.

BACKGROUND: Hepatitis B virus (HBV) is a cause of hepatocellular carcinoma (HCC). Interestingly, this process is not necessarily mediated through cirrhosis and may in fact involve oncogenic processes. Prior studies have suggested specific oncogenic gene expression pathways were affected by viral regulatory proteins. Thus, identifying these genes and associated pathways could highlight predictive factors for HCC transformation and has implications in early diagnosis and treatment. AIM: To elucidate HBV oncogenesis in HCC and identify potential therapeutic targets. METHODS: We employed our Search, Tag, Analyze, Resource platform to conduct a meta-analysis of public data from National Center for Biotechnology Information's Gene Expression Omnibus. We performed meta-analysis consisting of 155 tumor samples compared against 185 adjacent non-tumor samples and analyzed results with ingenuity pathway analysis. RESULTS: Our analysis revealed liver X receptors/retinoid X receptor (RXR) activation and farnesoid X receptor/RXR activation as top canonical pathways amongst others. Top upstream regulators identified included the Ras family gene rab-like protein 6 (RABL6). The role of RABL6 in oncogenesis is beginning to unfold but its specific role in HBV-related HCC remains undefined. Our causal analysis suggests RABL6 mediates pathogenesis of HBV-related HCC through promotion of genes related to cell division, epigenetic regulation, and Akt signaling. We conducted survival analysis that demonstrated increased mortality with higher RABL6 expression. Additionally, homeobox A10 (HOXA10) was a top upstream regulator and was strongly upregulated in our analysis. HOXA10 has recently been demonstrated to contribute to HCC pathogenesis in vitro. Our causal analysis suggests an in vivo role through downregulation of tumor suppressors and other mechanisms. CONCLUSION: This meta-analysis describes possible roles of RABL6 and HOXA10 in the pathogenesis of HBV-related HCC. RABL6 and HOXA10 represent potential therapeutic targets and warrant further investigation.