Studies suggest correlation between mycovirus containing Aspergillus flavus and leukemogenesis
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No methods or tests are available to detect susceptibility to acute lymphoblastic leukemia or lymphoblastic lymphomas. Likewise, there are no methodology or means to prevent these disorders.
We report that the products of a certain mycovirus containing Aspergillus flavus — isolated from the residence of a patient with ALL — react positively with the plasma of patients with this disease.
For these investigations, we used an enzyme-linked immunosorbent assay technique and plasma from 40 patients in complete remission or long-term survivors of this disease. Controls consisted of plasma from three groups — healthy individuals, patients with sickle cell disease, and individuals with solid tumors — and all were negative.
As highlighted in a paper published in 2020 in Journal of Pediatric Hematology/Oncology, electron microscopy showed the isolated organism to be infected with mycovirus, found within the organism and its culture.
A related study — published this year in Cancer Treatment and Research Communications — showed that when mononuclear leukocytes of patients with ALL in full remission and long-term survivors were exposed to the products of the above organism, these cells redeveloped cell surface phenotypes and genetic markers characteristic of ALL.
Flow cytometry and gene array techniques were used for the latter studies.
Extensive chemical evaluation of the culture of the isolated Aspergillus flavus revealed lack of aflatoxin production by this organism.
Infection by mycoviruses can inhibit the production of aflatoxin by the Aspergillus species.
Our time-related studies revealed that alteration in the cell surface phenotype and conversion to the characteristic ALL surface markers started approximately 6 hours after exposure of the cell from patients with ALL in remission to the product of the isolated organism, and the process was complete within 24 hours. Afterward, the changes persisted, without any further developments in the cells obtained from patients with ALL in complete remission. Again, controls showed no significant changes in their surface markers, regardless of the duration of incubation with the supernatant of the culture of mycovirus containing Aspergillus flavus.
Some of the genetic alterations observed in the ALL cells after exposure to the products of our certain organism included upregulation of JAK1 (12.87-fold), JAK2 (1.5-fold), JAK3 (2.73-fold), IKZF1 (10.12-fold), MCL1 (59.37-fold), MYC (14.19-fold) and HDAC1 (26.39-fold), as well as downregulation of PAX5 (3.05-fold).
Following incubation with the products of the above-mentioned organism, we noted a significant activation of transcription factor NF-B p65 in cells from patients with ALL. We observed no changes in the controls.
Positive and negative controls used for the supernatant of the culture of mycovirus containing Aspergillus flavus were aflatoxin and supernatant of the culture of Mycocladus corymbifera, respectively.
In separate studies, irradiation enhanced the observed cellular effects. The addition of Epstein Barr virus to the culture of the above organism did not alter the observed changes in the cells from patients with ALL in remission.
When we used fast protein liquid chromatography to analyze the supernatant of the culture of mycovirus containing Aspergillus flavus, we identified three peaks, the first of which was the most active. We utilized mass spectrometric analysis to analyze the protein content of the supernatant of the above organism.
Our findings suggest the particular isolated organism can be one of the infections predicted in the “two-hit” theory, which has been proposed for the development of ALL.
The two-hit theory suggests that ALL evolves in two discrete steps.
The suggested first step is in utero initiation by fusion gene formation or hyperdiploidy, which generates a preleukemic clone. The second step is the post-natal acquisition of secondary genetic changes, which drives conversion to the overt leukemia.
The second step has been proposed to be triggered in only a small percentage of those who have developed the first step genetic changes in utero, when later in life they are exposed to one or more common infections. This is thought to primarily occur among infants who have not experienced significant exposure to infections early in life.
Our findings regarding mycovirus containing Aspergillus flavus may indicate that isolated organism can be a consistent agent for the proposed infection portion of the two-hit theory, which hypothesizes generation of the leukemogenesis among susceptible individuals.
Published reports suggest that, based on the two-hit proposal, ALL can be preventable.
Except for the two papers cited above, no information regarding any possible correlation between mycoviruses — alone or in conjunction with Aspergillus flavus — and leukemia or other malignant disorders is available.
The above findings indirectly suggest that screening for and potentially prevention of ALL is possible. Further studies of mycoviruses and Aspergillus flavus and their relation to ALL are warranted.
References:
- Greaves M. Nat Rev Cancer. 2018;doi:10.1038/s41568-018-0015-6.
- Harrison CJ. Leukemia. 2021;doi:10.1038/s41375-021-01220-6.
- Schmidt FR. Appl Microbiol Biotechnol. 2009;doi:10.1007/s00253-009-2007-7.
- Schmidt S, et al. Appl Microbiol Biotechnol. 1986;24:248-252.
- Tebbi CK. Cancers (Basel). 2021;doi:10.3390/cancers13092256.
- Tebbi CK, et al. J Pediatr Hematol Oncol. 2020;doi:10.1097/MPH.0000000000001845.
- Tebbi CK, et al. Cancer Treat Res Commun. 2021;doi:10.1016/j.ctarc.2020.100279.
For more information:
Cameron K. Tebbi, MD, is director of Children’s Cancer Research Group in Tampa, Florida. He can be reached at ctebbi@childrenscancerresearchgrouplaboratory.org.
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