Antibody to Unique Mycovirus Discovered in Some ALL Patients

Acute Lymphoblastic Leukemia: Acute Lymphoblastic LeukemiaNewly published research shows children and adolescents with acute lymphoblastic leukemia (ALL) in full remission and long-term survivors who never have had any fungal infection uniformly have an antibody to a certain unique mycovirus containing Aspergillus flavus that, unlike other aspergillus species, does not produce any aflatoxin, which previous studies have suggested is the principal reason for cancer production by fungal agents. The antibody is to an organism that was isolated from the home of a patient with ALL. The mycovirus containing Aspergillus flavus culture was subjected to electron microscopy, purification, mass spectrometry, and chemical analysis. Together, the studies provide a new technique for the detection of ALL, according to the researchers who discovered the antibody. In light of the so-called “two hit” theory, which suggests ALL develops as a result of a genetic mutation during the fetal life and later exposure to an infectious agent after birth, this finding is of significance, according to the study's lead investigator, Cameron K. Tebbi, MD, Director of the Children's Cancer Research Group Laboratory in Tampa, Fla. Tebbi laid out the details of the discovery in an article, “Plasma of Acute Lymphoblastic Leukemia Patients React to the Culture of a Mycovirus Containing Aspergillus Flavus,” recently published in the Journal of Pediatric Hematology Oncology (2020; doi: 10.1097/MPH.0000000000001845).Cameron K. Tebbi, MD: Cameron K. Tebbi, MDWhile multiple genetic mutations have been reported, no constant infectious category has been identified, according to Tebbi. What's more, he noted the new findings may introduce a certain group of unusual infections as a constant agent in the development of ALL. The proteins and techniques reported by the researchers are patented in the U.S., Canada, European Union, Japan, Russia, and elsewhere. In fact, a companion article being penned by Tebbi et al, will show how the exposure of ALL mononuclear cells from patients in full remission—and not controls who were all negative—results in the redevelopment of characteristic genetic and cell surface phenotypes of ALL. The newly published article, meanwhile, significantly adds to the literature concerning leukemogenesis in ALL, said Tebbi, who recently shared additional insights regarding the findings with HemOnc Times. What inspired you to investigate this research question? “I have always been interested in cancer causes, especially as relates to leukemia. ALL is the most common childhood malignancies, accounting for approximately 25-30 percent of all cancers in this age group. It also occurs in adults, albeit with a much lower frequency. The etiology of ALL is not known. “As a part of investigating the environment of a child with ALL, I had isolated Aspergillus flavus from the home of a patient with ALL. The supernatant of culture of this organism was subjected to a significant number of studies, including electron microscopy and detailed chemical analysis. “These studies showed that this organism contains mycovirus. Interestingly, likely due to its mycovirus content, this Aspergillus flavus, unlike many other aspergillus species, does not produce any aflatoxin. Often, aflatoxins are suggested to be the principal reason for cancer production by fungal agents. “Among several theories for the mechanism of the development of B-cell acute lymphoblastic leukemia is the well-publicized ‘two-hit’ model, which suggests this disease arises through a two-step process, including predisposing genetic mutation and exposure to infections. While several genetic mutations are proposed, to date, no infection category has been suggested. “We have tested the culture of our isolated organism to evaluate if there are any antibodies against it in the plasma of ALL patients and controls and its direct effects on their peripheral blood mononuclear cells.” What were the key findings in your study? “When we evaluated the effects of the supernatant of culture of our mycovirus containing Aspergillus flavus in the plasma of 40 ALL patients, utilizing ELISA technique, we found the antibody in the plasma of these patients but not in controls. The three separate groups of controls included plasma of healthy individuals, as well as patients with solid tumors and sickle cell disease. “Our further studies revealed that exposure of the peripheral blood mononuclear cells (PBMCs) to the supernatant of the culture of our isolated organism reproduces cell surface phenotypes and genetic markers, characteristic of ALL, in the cells from patients with ALL in complete remission, and not in controls.” Were there any unexpected discoveries or surprising outcomes in your research? “The finding of the mycovirus within the body, hyphae, and culture of our isolated Aspergillus flavus was unexpected. The direct effects of culture products on the cell surface phenotypes and changes in the cellular genetic of ALL in remission and not controls (sickle cell patients) were not expected. “Lack of aflatoxin production by our Aspergillus flavus, which may be due to its mycovirus content, was initially a surprise. We had extensively searched the literature regarding reports of Aspergillus in residences of leukemia patients and had found a few reports. “These reports had not examined the direct effects of the culture of this organism against PBMCs, and there was no mention of mycovirus. In some of the prior reports, carcinogenic effects of Aspergillus were attributed to their mycotoxins or immunosuppressive activities, and not direct effect on the cells, as described in our studies. “To our knowledge, no reports of the effects of a mycovirus containing Aspergillus flavus culture products on the human cells in general, and cells from acute lymphoblastic leukemia in remission in particular, are currently available.” Is there anything about the results of your research that others might get wrong? “In our report, there is no intention to claim etiological cause and effect for exposure to the mycovirus containing Aspergillus flavus and the development of ALL. “Significantly larger and more detailed studies are needed to evaluate the effects of mycovirus containing Aspergillus flavus in details regarding its possible leukemogenesis.” What are the potential clinical implications, if any, of your research? “Currently, there are no reports of antibody against a constant organism in ALL. Indeed, no diagnostic plasma test for ALL exists. “Likewise, there are no methods to discriminately produce ALL cell surface phenotypes and genetic markers in cells from ALL patients in remission and not controls. “Our studies provide these techniques and have potential as a diagnostic or screening test. Also, our research can potentially introduce a constant organism for the ‘two- hit’ theory for leukemogenesis in acute lymphoblastic leukemia.” What further research needs to be done on this topic? “Our study is only the first step in the evaluation of a certain mycovirus containing Aspergillus Flavus in acute lymphoblastic leukemia. A number of studies are needed to confirm the role of this organism and its mechanisms of action in this disease.” Is there anything else about your research that you would like to share with HemOnc Times readers? “The current research is only an early-stage study and significant work is necessary to better understand the role and mechanism of action of a mycovirus containing Aspergillus flavus in leukemogenesis. Chuck Holt is a contributing writer.

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