Mycoviruses in Fungi: Carcinogenesis of Fungal Agents May Not Always Be Mycotoxin Related

**Background:** This narrative review examines the potential role of mycoviruses—viruses that infect fungi—in carcinogenesis, challenging the traditional focus on mycotoxins as the primary carcinogenic agents from fungi. The author notes that while mycotoxins like aflatoxin are well-established hepatocarcinogens, epidemiological data show increased cancer rates in occupations with high fungal exposure (e.g., agricultural workers) and an inverse association between allergies and certain cancers. Recent studies have identified a mycovirus-containing Aspergillus flavus (MCAF) isolated from the home of a patient with acute lymphoblastic leukemia (ALL). This MCAF does not produce aflatoxin. In vitro exposure of mononuclear cells from ALL patients in remission to MCAF products re-induced cell surface and genetic markers characteristic of active ALL, whereas controls showed no changes. Additionally, ALL patients, but not controls, had antibodies to MCAF products. These findings suggest a possible infectious trigger for the second hit in the two-hit model of pediatric ALL, where in utero genetic initiation is followed by postnatal infection-driven secondary mutations.

**Methods:** This is a narrative review summarizing existing literature on fungal carcinogenesis, mycotoxins, and mycoviruses. The author synthesizes data from epidemiological studies, in vitro experiments, and molecular biology reports. Key cited studies include those showing the re-induction of ALL markers by MCAF in remission patients (reference 91) and the presence of anti-MCAF antibodies in ALL patients (reference 92). The review also covers the metabolism of aflatoxins, the diversity of mycoviruses, and their effects on fungal hosts.

**Key Results:** The review reports that MCAF exposure in vitro re-develops ALL phenotypes in remission patients' mononuclear cells, but not in controls. ALL patients uniformly have antibodies to MCAF products. The MCAF strain was isolated from an ALL patient's home and does not produce aflatoxin. The author notes that 30–80% of fungal species contain mycoviruses, and mycoviruses can alter fungal phenotypes, including loss of aflatoxin production. For example, mycovirus infection in Aspergillus flavus can lead to cessation of aflatoxin production. The review also details that mycoviruses can induce TLR3-mediated inflammatory responses, as seen with Malassezia-derived MrV40 mycovirus. Epidemiological data cited include increased cancer rates in agricultural workers and lower rates of certain cancers in allergic individuals.

**Clinical Implications:** The review proposes that mycovirus-containing fungi, particularly MCAF, may be an infectious trigger for ALL in genetically predisposed individuals. This challenges the exclusive focus on mycotoxins in fungal carcinogenesis and opens new avenues for research into the etiology of leukemia and other cancers. The author emphasizes that the role of mycoviruses in human health is poorly evaluated and warrants further investigation. If confirmed, this could lead to preventive strategies, such as avoiding exposure to specific mycovirus-containing fungi, and potentially new therapeutic targets. The review also highlights the need to study mycoviruses in conjunction with their fungal hosts, as they may modulate pathogenicity and carcinogenicity.