Department of Veterinary Internal Medicine, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo, Japan.
Laboratory of Clinical Diagnostics, School of Veterinary Medicine, Azabu University, Kanagawa, Japan.
J Vet Med Sci. 2024 Jul 2;86(7):737-743. doi: 10.1292/jvms.23-0371. Epub 2024 Jun 3.
Non-neoplastic bone marrow disorders are main causes of non-regenerative anemia in dogs. Despite the high incidence of the diseases, their molecular pathophysiology has not been elucidated. We previously reported that Miniature Dachshund (MD) was a predisposed breed to be diagnosed with non-neoplastic bone marrow disorders in Japan, and immunosuppressive treatment-resistant MDs showed higher number of platelets and morphological abnormalities in peripheral blood cells. These data implied that treatment-resistant MDs might possess distinct pathophysiological features from treatment-responsive MDs. Therefore, we conducted transcriptomic analysis of bone marrow specimens to investigate the pathophysiology of treatment-resistant MDs. Transcriptomic analysis comparing treatment-resistant MDs and healthy control dogs identified 179 differentially expressed genes (DEGs). Pathway analysis using these DEGs showed that "Wnt signaling pathway" was a significantly enriched pathway. We further examined the expression levels of DEGs associated with Wnt signaling pathway and confirmed the upregulation of AXIN2 and CCND2 and the downregulation of SFRP2 in treatment-resistant MDs compared with treatment-responsive MDs and healthy control dogs. This alteration implied the activation of Wnt signaling pathway in treatment-resistant MDs. The activation of Wnt signaling pathway has been reported in human patients with myelodysplastic syndrome (MDS), which is characterized by dysplastic features of blood cells. Therefore, the results of this study implied that treatment-resistant MDs have distinct molecular pathological features from treatment-responsive MDs and the pathophysiology of treatment-resistant MDs might be similar to that of human MDS patients.
非肿瘤性骨髓疾病是犬再生障碍性贫血的主要原因。尽管这些疾病的发病率很高，但它们的分子病理生理学尚未阐明。我们之前曾报道，迷你腊肠犬（MD）是日本易患非肿瘤性骨髓疾病的品种，且免疫抑制治疗耐药的 MD 在外周血细胞中表现出更高的血小板数量和形态异常。这些数据表明，治疗耐药的 MD 可能具有与治疗敏感的 MD 不同的病理生理特征。因此，我们对骨髓标本进行了转录组分析，以研究治疗耐药 MD 的病理生理学。对治疗耐药的 MD 和健康对照犬进行比较的转录组分析鉴定出 179 个差异表达基因（DEG）。使用这些 DEG 进行的途径分析表明，“Wnt 信号通路”是一个显著富集的途径。我们进一步检查了与 Wnt 信号通路相关的 DEG 的表达水平，并证实与治疗敏感的 MD 和健康对照犬相比，治疗耐药的 MD 中 AXIN2 和 CCND2 的表达上调，而 SFRP2 的表达下调。这种改变暗示了 Wnt 信号通路在治疗耐药的 MD 中的激活。Wnt 信号通路的激活已在人类骨髓增生异常综合征（MDS）患者中报道，其特征是血细胞的发育不良特征。因此，这项研究的结果表明，治疗耐药的 MD 具有与治疗敏感的 MD 不同的分子病理特征，治疗耐药的 MD 的病理生理学可能与人类 MDS 患者的相似。
