Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia
Acquired FANCA dysfunction and cytogenetic instability in adult acute myelogenous leukemia
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DOI：
10.1182/blood-2002-09-2781
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发表时间：
2003-07-01
期刊：
影响因子：
20.3
通讯作者：
Bagby, GC
中科院分区：
文献类型：
--
作者：
Lensch, MW;Tischkowitz, M;Bagby, GC
在范可尼贫血的儿童和成人中发展的骨髓增生异常和白血病干细胞克隆普遍具有复杂的细胞遗传学异常。这些异常通常是重复性缺失或染色体丢失，涉及与烷化剂诱导的继发性急性白血病患者的骨髓细胞中所描述的频率完全相同的染色体。推理获得性范可尼贫血蛋白功能障碍可能有助于继发性急性髓细胞性白血病（AML）细胞的细胞遗传学不稳定性，我们分析了白血病细胞轴承特征复杂的细胞遗传学缺陷，从一个68岁的男子，其淋巴母细胞没有表现出范可尼贫血的证据。与淋巴母细胞不同，该髓性白血病细胞系（UoC-M1）对丝裂霉素C（MMC）和二环氧丁烷（DEB）高度敏感，并表现出核FANCA、FANCG和FANCD 2-L的显著减少。FANCA的逆转录病毒转导显著降低MMC敏感性，但FANCF，FANCG和FANCC没有。FANCA的过表达恢复了FANCA和FANCG的水平，而FANCG或FANCC的过表达没有恢复FANCA水平。细胞质FANCA、FANCG、FANCC和细胞核FANCD 2的分子量均正常。FANCA和FANCG的所有外显子进行测序，并没有突变被发现。我们得出结论，扰动尚未确定的因素，管理FANCA的结合活性或细胞内定位可能会促进细胞遗传学的不稳定性和克隆进展的AML患者谁没有范可尼贫血。(C)2003年，美国血液学会。
Myelodysplastic and leukemic stem cell clones that evolve in children and adults with Fanconi anemia universally bear complex cytogenetic abnormalities. The abnormalities are generally recurring deletions or chromosomal loss and involve precisely the same chromosomes with the same frequency as has been described in marrow cells from patients with secondary acute leukemia induced by alkylating agents. Reasoning that acquired Fanconi anemia protein dysfunction might contribute to cytogenetic instability in secondary acute myelogenous leukemia (AML) cells, we analyzed leukemic cells bearing characteristic complex cytogenetic defects obtained from a 68-year-old man whose lymphoblasts showed no evidence of Fanconi anemia. Unlike the lymphoblasts, this myeloid leukemia cell line (UoC-M1) was hypersensitive to mitomycin-C (MMC) and diepoxybutane (DEB) and exhibited a marked decrease in nuclear FANCA, FANCG, and FANCD2-L. Retroviral transduction of FANCA significantly reduced MMC sensitivity but FANCF, FANCG, and FANCC did not. Overexpression of FANCA restored levels of both FANCA and FANCG, whereas overexpression of FANCG or FANCC did not restore FANCA levels. The molecular mass of cytoplasmic FANCA, FANCG, FANCC, and nuclear FANCD2 were normal. All exons of FANCA and FANCG were sequenced, and no mutations were found. We conclude that perturbations of as yet unidentified factors that govern the binding activity or intracellular localization of FANCA may promote cytogenetic instability and clonal progression in patients with AML who do not have Fanconi anemia. (C) 2003 by The American Society of Hematology.