Mycovirus Containing Aspergillus flavus and Acute Lymphoblastic Leukemia: Carcinogenesis beyond Mycotoxin Production

Carcinogenic effects of Aspergillus spp. have been well established and generally attributed to a variety of mycotoxin productions, particularly aflatoxins. It is known that most carcinogenic mycotoxins, with the exception of fumonisins, are genotoxic and mutagenic, causing chromosomal aberrations, micronuclei, DNA single-strand breaks, sister chromatid exchange, unscheduled DNA synthesis etc. Some Aspergillus spp. are infected with mycoviruses which can result in loss of aflatoxin production. The effects of mycovirus containing Aspergillus on human health have not been fully evaluated. Recent studies in patients with acute lymphoblastic leukemia, in full remission, have revealed the existence of antibody to the products of a certain Aspergillus flavus isolate which harbored an unknown mycovirus. Exposure of blood mononuclear cells from these patients, but not controls, to the products of this organism had reproduced cell surface phenotypes and genetic markers, characteristic of acute lymphoblastic leukemia. Carcinogenic effects of Aspergillus spp. may not always be mycotoxin related and this requires further investigation.

TopBP1 is required at mitosis to reduce transmission of DNA damage to G1 daughter cells

Genome integrity is critically dependent on timely DNA replication and accurate chromosome segregation. Replication stress delays replication into G2/M, which in turn impairs proper chromosome segregation and inflicts DNA damage on the daughter cells. Here we show that TopBP1 forms foci upon mitotic entry. In early mitosis, TopBP1 marks sites of and promotes unscheduled DNA synthesis. Moreover, TopBP1 is required for focus formation of the structure-selective nuclease and scaffold protein SLX4 in mitosis. Persistent TopBP1 foci transition into 53BP1 nuclear bodies (NBs) in G1 and precise temporal depletion of TopBP1 just before mitotic entry induced formation of 53BP1 NBs in the next cell cycle, showing that TopBP1 acts to reduce transmission of DNA damage to G1 daughter cells. Based on these results, we propose that TopBP1 maintains genome integrity in mitosis by controlling chromatin recruitment of SLX4 and by facilitating unscheduled DNA synthesis.

Evaluation of bendamustine in combination with fludarabine in primary chronic lymphocytic leukemia cells

Key Points The fludarabine and bendamustine combination is cytotoxic to CLL cells even in the presence of a protective microenvironment. H2AX activation was maximum with the combination, and unscheduled DNA synthesis induced by bendamustine was blocked by fludarabine.