Aryl hydrocarbon receptor nuclear translocator (ARNT) isoforms control lymphoid cancer cell proliferation through differentially regulating tumor suppressor p53 activity.

The aryl hydrocarbon receptor nuclear translocator (ARNT) is involved in xenobiotic and hypoxic responses, and we previously showed that ARNT also regulates nuclear factor-κB (NF-κB) signaling by altering the DNA binding activity of the RelB subunit. However, our initial study of ARNT-mediated RelB modulation was based on simultaneous suppression of the two ARNT isoforms, isoform 1 and 3, and precluded the examination of their individual functions. We find here that while normal lymphocytes harbor equal levels of isoform 1 and 3, lymphoid malignancies exhibit a shift to higher levels of ARNT isoform 1. These elevated levels of ARNT isoform 1 are critical to the proliferation of these cancerous cells, as suppression of isoform 1 in a human multiple myeloma (MM) cell line, and an anaplastic large cell lymphoma (ALCL) cell line, triggered S-phase cell cycle arrest, spontaneous apoptosis, and sensitized cells to doxorubicin treatment. Furthermore, co-suppression of RelB or p53 with ARNT isoform 1 prevented cell cycle arrest and blocked doxorubicin induced apoptosis. Together our findings reveal that certain blood cancers rely on ARNT isoform 1 to potentiate proliferation by antagonizing RelB and p53-dependent cell cycle arrest and apoptosis. Significantly, our results identify ARNT isoform 1 as a potential target for anticancer therapies.

Analysis of HLA association among North Indian HIV-positive individuals co-infected with Mycobacterium tuberculosis.

BACKGROUND: Genetic variation in HLA genes influence the immune response and may thus contribute to differential development of tuberculosis (TB) in HIV-infected individuals. The study was designed to determine whether HLA polymorphisms influence the development of Mycobacterium tuberculosis infection in HIV-infected individuals. MATERIALS AND METHODS: Fifty HIV-positive individuals without TB (HIV+TB-), 50 HIV patients co-infected with TB (HIV+TB+) and 50 control subjects (HIV-TB-) were analyzed for HLA Class I and II polymorphisms. RESULTS: In HLA Class II, frequency of occurrence of DRB1*13 (OR 3.165, CI 1.176-8.518, P value 0.019), DRB5 (OR 2.253, CI 1.011-5.019, P value 0.045) and DQB1*06 (OR 2.705, CI 1.197-6.113, P value 0.016) were increased in HIV+TB+compared to HIV+TB-. HLA DQB1*02 (OR 0.436, CI 0.185-1.029, P value 0.05) on the other hand conferred a protective role. In HLA Class I, frequency of B*15 (OR 2.705, CI 1.040-7.036, P value 0.038) was increased, whereas B*51 (OR 0.148, CI 0.031-0.706, P value 0.007) was decreased in HIV+TB+group compared to HIV+TB-. These differences however were not significant when compared with healthy controls. CONCLUSION: HLA polymorphisms independently did not account for the susceptibility to either of the disease mostly, although they seem to play a role once the infection(s) has established in a particular individual. Further studies are needed on a larger sample size to confirm these observations.