Molecular pathogenesis of Fanconi anemia

范可尼贫血的分子发病机制

• 批准号: 16590928
• 负责人: YAMASHITA Takayuki
• 金额: $ 2.37万
• 依托单位: Gunma University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590928/
• 关键词: Fanconi anemia; bone marrow failure; DNA repair; genetic reversion; somatic mosaicism; methylation; tumor suppressor gene; シャペロン; ユビキチン化; プロテアソーム

Fanconi anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure and congenital anomalies. Although an increasing number of reports suggest that reverse mosaicism noted in peripheral blood lymphocytes (PBL) is associated with mild hematopoietic failure in FA, direct examination of myeloid cells have been done in few cases. We found a patient with prolonged mild pancytopenia in whom proliferation of revertant cells was detected in mature myeloid cells but not in PBL. While this patient had inherited heterozygous mutations, 2546delC and 3720-3724del, in the major Fanconi anemia gene FANCA, lymphoblastoid cells from the patient had 2546C>T instead of 2546delC, resulting in expression of a functional missense protein. Since the identical reversion was detected in polymorphonuclear granulocytes and mononuclear phagocytes, sustained hematopoiesis in the patient is attributed to selective growth advantage of revertant myeloid cells. It is noteworthy t … More hat such a myeloid lineage-selective mosaicism is overlooked in routine examination of PBL. Recognition of this status will expand the role of reverse mosaicism in the pathophysiology of FA. Bone marrow failure in FA often shows progression to myelodysplastic syndrome (MDS) and leukemia, which may be attributed to mutations of oncogenes and tumor suppressor genes based on DNA repair deficiency. However, specific mutations of these genes have not been identified in FA leukemic cells. We hypothesized that epigenetic abnormalities may be associated with the pathophysiology of FA. To address this question, we analyzed promoter methylation of five tumor suppressor genes, p15, p16. DAP kinase, RAR-β, E-cadherin. The results showed that 8 of 11 patients (72.7%) had hypermethylation in one or more of these genes. The methylation abnormalities were observed more frequently in patients with MDS than in those without MDS. These results suggest that epigenetic abnormalities might be involbed in leukmogensis in FA. Less

范可尼贫血（FA）是一种以骨髓衰竭和先天性畸形为特征的遗传异质性疾病。虽然越来越多的报告表明，在外周血淋巴细胞（PBL）中注意到的反向嵌合体与FA中的轻度造血功能衰竭有关，但在少数情况下进行了骨髓细胞的直接检查。我们发现一个病人有长期的轻度全血细胞减少症，其中在成熟的骨髓细胞中检测到回复突变细胞的增殖，但在PBL中没有。虽然该患者在主要范可尼贫血基因FANCA中具有遗传杂合突变2546 delC和3720- 3724 del，但来自患者的淋巴母细胞具有2546 C>T而不是2546 delC，导致功能性错义蛋白的表达。由于在多形核粒细胞和单核吞噬细胞中检测到相同的回复，因此患者持续的造血归因于回复突变骨髓细胞的选择性生长优势。值得注意的是， ...更多信息 这种髓系选择性嵌合现象在PBL的常规检查中被忽略了。认识到这一地位将扩大反镶嵌在FA的病理生理学的作用。FA中的骨髓衰竭常表现为骨髓增生异常综合征（MDS）和白血病的进展，这可能归因于基于DNA修复缺陷的癌基因和肿瘤抑制基因的突变。然而，这些基因的特定突变尚未确定在FA白血病细胞。我们推测表观遗传异常可能与FA的病理生理学有关。为了解决这个问题，我们分析了五个肿瘤抑制基因，p15，p16的启动子甲基化。DAP激酶、RAR-β、E-钙粘蛋白。结果显示，11例患者中有8例（72.7%）在这些基因中的一个或多个中存在高甲基化。MDS患者的甲基化异常率高于非MDS患者。这些结果表明，表观遗传异常可能参与了白血病的FA。少

项目成果

ABT1‐associated protein (ABTAP), a novel nuclear protein conserved from yeast to mammals, represses transcriptional activation by ABT1

• DOI: 10.1002/jcb.20114
• 发表时间: 2004-11
• 期刊: Journal of Cellular Biochemistry
• 影响因子: 4
• 作者: T. Oda;A. Fukuda;H. Hagiwara;Y. Masuho;M. Muramatsu;K. Hisatake;T. Yamashita

Molecular Mechanisms of Fanconi Anemia

范可尼贫血的分子机制

• 发表时间: 2006
• 作者: Yamashita T;et a1.
• 通讯作者: et a1.

Myeloid lineage-selective growth of revertant cells in Fanconi anemia.

范可尼贫血中回复细胞的骨髓谱系选择性生长。

• 发表时间: 2006
• 期刊: British Journal of Haematology 132
• 作者: Hamanoue S;Oda T;Yamashita T et al.
• 通讯作者: Yamashita T et al.

Identification and characterization of the major Fanconi anemia gene FANCA in the Japanese population.

日本人群中主要范可尼贫血基因 FANCA 的鉴定和特征分析。

• 发表时间: 2004
• 期刊: Human Mutation 24
• 作者: Yagasaki H;Yamashita T;et al.
• 通讯作者: et al.