RESUMO
We identified a three-generation Russian family with Lynch syndrome with a novel germline variant of the MSH6 gene. An 84-year-old female was diagnosed with endometrial adenocarcinoma at the age of 49 years. Her son was diagnosed with colorectal tubular adenoma at the age of 32 years. A germline nonsense variant (c.484 G > T:p.Gly162Ter) in exon 3 of the MSH6 gene was revealed by whole-exome sequencing. Sanger sequencing confirmed the cosegregation of the MSH6 nonsense variant in family members.
RESUMO
Leukemic cells from different patients exhibit different sensitivity to anticancer drugs including doxorubicin (DOX). Resistance to chemotherapy decreases efficacy of the treatment and promotes cancer recurrence and metastases. One of the approaches to overcome drug resistance includes E2F1-mediated regulation of the Ñ73 protein that belongs to the Ñ53 family. Its ΔNp73 isoform exhibits pro-oncogenic effects, and TAp73 - anti-oncogenic effects. Human cytomegalovirus (HCMV), often found in tumors, suppresses pro-apoptotic pathways and E2F1/p73 in particular. The activity of E2F1 and p73 transcription factors is linked to metabolism of biogenic polyamines. Therefore, it could be suggested that compounds that target polyamine-metabolizing enzymes can sensitize HCMV-infected hematological malignancies to doxorubicin. Here we report that HCMV infection of ТÐÐ -1 monocytic leukemic cells considerably elevates E2F1 levels and shifts the balance between the Ñ73 isoforms towards ΔNp73 leading to survival of DOX-treated leukemic cells. In contrast, MDL72.527, an inhibitor of polyamine catabolism, decreases ΔNp73/ТÐÑ73 ratio and thus restores sensitivity of the cells to DOX. Our findings indicate the combination of doxorubicin and MDL72.527 may present a novel strategy for therapy of leukemia in patients with and without HCMV infection.
