Lymphoid malignancies ARNT unstoppable

(ARNT; also known as hypoxia inducible factor 1-β) is a member of the basic-helix-loop-helix-Per/ARNT/Sim (bHLH-PAS) family of transcription factors. ARNT is a common binding partner in this family and predominantly heterodimerizes with HIF-1α, or the aryl hydrocarbon receptor (AHR), and aids in the recognition of their respective DNA binding sequences [1]. The AHR has been recognized for decades as the mediator of xenobiotic responses to environmental pollutant exposure, which act as ligands for AHR, including polycyclic aromatic hydrocarbons (e.g. benzo(a)pyrene) and halogenated aromatic hydrocarbons such as the high affinity AHR ligand 2,3,7,8-tetrachlorodibenzodioxin [1]. Additionally, AHR signaling plays a role in normal physiology where AHR induction occurs through binding endogenous and natural ligands, most notably tryptophan catabolites [2]. Importantly, physiological AHR signaling is involved in immunomodulation by controlling processes like hematopoiesis, B and T cell differentiation, and immune tolerance [3, 4]. Consequently, interference of normal AHR signaling by environmental toxicants influences the development of autoimmune disorders, including lymphoid malignancies, the incidence of which increases with age. However, little is known about the role of ARNT in AHR immune signaling. Initial studies by our laboratory, and others, into the regulatory role of ARNT in AHR-mediated immunomodulation have suggested that ARNT is an integral cofactor in different immune cell signaling pathways, including NF-κB signaling [5, 6]. ARNT is expressed as two isoforms, isoform 1 and 3, which differ in only 15 amino acids present in isoform 1. Nonetheless, ARNT cellular function had not been considered as the combined activity of the two ARNT isoforms. In our recent Oncotarget priority report it was observed that normal lymphocytes harbor equal levels of isoform 1 and 3, whereas lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1 to isoform 3 ratios [7]. Through targeted suppression, using isoform specific RNAi to modulate the ARNT isoform ratio, a requirement for ARNT isoform 1 in sustaining proliferation and supporting cell survival was uncovered [7]. We observed that in the absence of Editorial ARNT isoform 1, malignant blood cells stopped proliferating due to S-phase cell cycle arrest that is ultimately due to increased p53 stability and activation [7]. Importantly, these phenotypes are specific to suppression of isoform 1, whereas suppression of isoform 3 has no impact on cell proliferation. Subsequently, we have found that suppression of the predominant isoform 1, in various lymphoid cancers, allows basally nuclear AHR to more readily associate with isoform 3, in turn …