Diagnosis and Early Prediction of Lymphoma Using High-Throughput Clonality Analysis of Bovine Leukemia Virus-Infected Cells

Okagawa, Tomohiro; Shimakura, Honami; Konnai, Satoru; Saito, Masumichi; Matsudaira, Takahiro; Nao, Naganori; Yamada, Shinji; Murakami, Kenji; Maekawa, Naoya; Shiro, Motoo; Ohashi, Kazuhiko

doi:10.1128/spectrum.02595-22

Cited by 9 publications

(6 citation statements)

References 25 publications

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“…A scheme for somatic mutation analysis in cattle with EBL development. Thirty-six EBL cattle collected in previous studies [37, 38] were used for the mutation analysis. Blood and tumor samples derived from the same EBL cases were examined to identify variants in their genome using amplicon sequencing that targeted 21 cancer-related genes.…”

Section: Resultsmentioning

confidence: 99%

“…The information on EBL cases used in this study are listed in Table S1. All cases were diagnosed as EBL in a domestic livestock hygiene service center and meat inspection center in Japan, and they were kindly provided for research use in the previous studies [37, 38]. To select EBL cases not showing leukemic signs, it was confirmed that lymphocyte counts or clonality values measured by the RAISING-CLOVA method [38] were low in the blood (Table S1).…”

Section: Methodsmentioning

confidence: 99%

“…All cases were diagnosed as EBL in a domestic livestock hygiene service center and meat inspection center in Japan, and they were kindly provided for research use in the previous studies [37, 38]. To select EBL cases not showing leukemic signs, it was confirmed that lymphocyte counts or clonality values measured by the RAISING-CLOVA method [38] were low in the blood (Table S1). In cases #1–32, peripheral blood mononuclear cells (PBMCs) were isolated from blood samples using Percoll (GE Healthcare Life Sciences, Little Chalfont, UK) density gradient centrifugation for DNA extraction.…”

Section: Methodsmentioning

confidence: 99%

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Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis

Nishimori,

Andoh,

Matsuura

et al. 2024

Preprint

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Oncogenic transformation of normal cells is caused by mutations and chromosomal abnormalities in cancer-related genes. Enzootic bovine leukosis (EBL) is a malignant B-cell lymphoma caused by bovine leukemia virus (BLV) infection in cattle. Although a small fraction of BLV-infected cattle develops EBL after a long latent period, the mechanisms for oncogenesis in EBL cattle remain largely unknown. In this study, we analyzed the types and patterns of somatic mutations in cancer cells from 36 EBL cases, targeting 21 cancer-related genes. Various somatic mutations were identified in 8 genes, TP53, NOTCH1, KMT2D, CREBBP, KRAS, PTEN, CARD11, and MYD88. In addition, TP53 gene was found to be mutated in 69.4% of EBL cases, with most being biallelic mutations. In some cases, associations were observed between the ages at which cattle had developed EBL and somatic mutation patterns; young onset of EBL possibly occurs due to congenital mutations, high impact mutations affecting protein translation, and biallelic mutations. Furthermore, nucleotide substitution patterns indicated that cytosine at CpG sites tended to be converted to thymine in many EBL cases, which was considered to be the result of spontaneous deamination of 5-methylctosine. These results demonstrate how somatic mutations have occurred in cancer cells leading to EBL development, thereby explaining its pathogenic mechanism. These findings will contribute to a better understanding and future elucidation of disease progression in BLV infection.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis

Nishimori,

Andoh,

Matsuura

et al. 2024

Preprint

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“…A new method called RAISING-CLOVA has recently been proposed to be useful for the early prediction of EBL onset [ 23 ]. This method was used to analyze the clonality of BLV-infected cells (Cv) in 4 sheep with experimental BLV infection and showed that Cv increased before or at the EBL onset.…”

Section: Discussionmentioning

confidence: 99%

Serum bta-miRNA-375 as a potential biomarker for the early diagnosis of enzootic bovine leukosis

Murakami,

Matsunaga,

Matsuzaki

et al. 2024

PLoS ONE

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To identify a biomarker for the early diagnosis of enzootic bovine leukosis (EBL) caused by bovine leukemia virus (BLV), we investigated the expression of a microRNA, bta-miR-375, in cattle serum. Using quantitative reverse-transcriptase PCR analysis, we measured bta-miR-375 levels in 27 samples from cattle with EBL (EBL cattle), 45 samples from animals infected with BLV but showing no clinical signs (NS cattle), and 30 samples from cattle uninfected with BLV (BLV negative cattle). In this study, we also compared the kinetics of bta-miR-375 with those of the conventional biomarkers of proviral load (PVL), lactate dehydrogenase (LDH), and thymidine kinase (TK) from the no-clinical-sign phase until EBL onset in three BLV-infected Japanese black (JB) cattle. Bta-miR-375 expression was higher in NS cattle than in BLV negative cattle (P < 0.05) and greater in EBL cattle than in BLV negative and NS cattle (P < 0.0001 for both comparisons). Receiver operating characteristic curves demonstrated that bta-miR-375 levels distinguished EBL cattle from NS cattle with high sensitivity and specificity. In NS cattle, bta-miR-375 expression was increased as early as at 2 months before EBL onset—earlier than the expression of PVL, TK, or LDH isoenzymes 2 and 3. These results suggest that serum miR-375 is a promising biomarker for the early diagnosis of EBL.

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“…Determining the risk of developing EBL by PVL alone is challenging, although PVL can be a rough index. Combination with other hematological markers or measures, such as clonality analysis of BLV-infected cells [ 21 ], which cannot readily perform in the field, would be needed for reliable diagnosis of EBL cattle. The negative binomial regression model built in this study suggested a correlation between MNT and PVL, consistent with other studies [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Estimation of the proviral load in Japanese Black cattle infected with bovine leukemia virus by statistical modeling

IWAMOTO,

KOREEDA,

IINO

et al. 2024

The Journal of Veterinary Medical Science

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Enzootic bovine leukosis (EBL) is B-cell lymphoma in cattle caused by bovine leukemia virus (BLV) infection. The incidence of EBL has been increasing since 1998 in Japan, resulting in significant economic losses for farms. The BLV genome integrates with the host genome as provirus, leading to sustainably infection. Although most of the BLV-infected cattle are aleukemic, some cattle cause persistent lymphocytosis (PL) and subsequently develop EBL. Recent reports suggest the association between the risk for the transmission of BLV and the developing EBL and the proviral load (PVL) in BLV-infected cattle, which cannot measure readily in the field. This study aims to build a statistical model for predicting PVL of BLV-infected asymptomatic or PL cattle based on data accessible in the field. Five negative binomial regression models with different linear predictors were built and compared for the predictability of PVL. Consequently, the model with two explanatory variables (age in months and logarithm of lymphocyte count) was selected as the best model. The model can be used in the field as a cost-beneficial supporting tool to estimate the risk of transmission of BLV and developing EBL in infected cattle.

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Diagnosis and Early Prediction of Lymphoma Using High-Throughput Clonality Analysis of Bovine Leukemia Virus-Infected Cells

Abstract: Bovine leukemia virus (BLV) infection causes aggressive B-cell lymphoma in cattle and sheep. The virus has spread to farms around the world, causing significant economic damage to the livestock industry.

Cited by 9 publications

References 25 publications

Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis

Effect of C-to-T transition at CpG sites on tumor suppressor genes in tumor development in cattle evaluated by somatic mutation analysis in enzootic bovine leukosis

Serum bta-miRNA-375 as a potential biomarker for the early diagnosis of enzootic bovine leukosis

Estimation of the proviral load in Japanese Black cattle infected with bovine leukemia virus by statistical modeling

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