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Mosaicism in Fanconi anemia: concise review and evaluation of published cases with focus on clinical course of blood count normalization.
Annals of Hematology ( IF 3.5 ) Pub Date : 2020-02-17 , DOI: 10.1007/s00277-020-03954-2 Eileen Nicoletti 1 , Gayatri Rao 1 , Juan A Bueren 2, 3, 4 , Paula Río 2, 3, 4 , Susana Navarro 2, 3, 4 , Jordi Surrallés 3, 5, 6 , Grace Choi 1 , Jonathan D Schwartz 1
Annals of Hematology ( IF 3.5 ) Pub Date : 2020-02-17 , DOI: 10.1007/s00277-020-03954-2 Eileen Nicoletti 1 , Gayatri Rao 1 , Juan A Bueren 2, 3, 4 , Paula Río 2, 3, 4 , Susana Navarro 2, 3, 4 , Jordi Surrallés 3, 5, 6 , Grace Choi 1 , Jonathan D Schwartz 1
Affiliation
Fanconi anemia (FA) is a DNA repair disorder resulting from mutations in genes encoding for FA DNA repair complex components and is characterized by variable congenital abnormalities, bone marrow failure (BMF), and high incidences of malignancies. FA mosaicism arises from reversion or other compensatory mutations in hematopoietic cells and may be associated with BMF reversal and decreased blood cell sensitivity to DNA-damaging agents (clastogens); this sensitivity is a phenotypic and diagnostic hallmark of FA. Uncertainty regarding the clinical significance of FA mosaicism persists; in some cases, patients have survived multiple decades without BMF or hematologic malignancy, and in others hematologic failure occurred despite the presence of clastogen-resistant cell populations. Assessment of mosaicism is further complicated because clinical evaluation is frequently based on clastogen resistance in lymphocytes, which may arise from reversion events both in lymphoid-specific lineages and in more pluripotent hematopoietic stem/progenitor cells (HSPCs). In this review, we describe diagnostic methods and outcomes in published mosaicism series, including the substantial intervals (1-6 years) over which blood counts normalized, and the relatively favorable clinical course in cases where clastogen resistance was demonstrated in bone marrow progenitors. We also analyzed published FA mosaic cases with emphasis on long-term clinical outcomes when blood count normalization was identified. Blood count normalization in FA mosaicism likely arises from reversion events in long-term primitive HSPCs and is associated with low incidences of BMF or hematologic malignancy. These observations have ramifications for current investigational therapeutic programs in FA intended to enable gene correction in long-term repopulating HSPCs.
中文翻译:
范可尼贫血的镶嵌术:简报和评估已发表病例,重点是血细胞计数正常化的临床过程。
范可尼贫血(FA)是一种DNA修复疾病,是由编码FA DNA修复复合物成分的基因突变导致的,其特征是先天性异常,骨髓衰竭(BMF)和恶性肿瘤高发。FA镶嵌病是由造血细胞的逆转或其他补偿性突变引起的,可能与BMF逆转和血细胞对DNA破坏剂(破伤源)的敏感性降低有关;这种敏感性是FA的表型和诊断标志。关于FA镶嵌症的临床意义的不确定性仍然存在;在某些情况下,患者可以存活数十年而无BMF或血液系统恶性肿瘤;而在另一些情况下,尽管存在抗卡洛司汀耐药的细胞群,但仍发生血液学衰竭。由于临床评估通常基于淋巴细胞中的克拉斯蛋白酶抗性,因此镶嵌性的评估更加复杂,这可能是由于淋巴特异性谱系和更全能的造血干/祖细胞(HSPC)中的逆转事件引起的。在这篇综述中,我们描述了已发表的镶嵌术系列中的诊断方法和结果,包括血液计数正常化的相当大的间隔(1-6年),以及在骨髓祖细胞中显示出对克拉斯托原耐药的情况下相对有利的临床过程。我们还分析了已公布的FA镶嵌病例,重点是在确定血细胞计数正常化后的长期临床结局。FA镶嵌症中的血球计数正常化可能源于长期原始HSPC中的逆转事件,并且与BMF或血液系统恶性肿瘤的发生率低相关。这些观察结果对目前FA中的研究性治疗方案产生了影响,该方案旨在在长期重新繁殖的HSPC中进行基因校正。
更新日期:2020-02-18
中文翻译:
范可尼贫血的镶嵌术:简报和评估已发表病例,重点是血细胞计数正常化的临床过程。
范可尼贫血(FA)是一种DNA修复疾病,是由编码FA DNA修复复合物成分的基因突变导致的,其特征是先天性异常,骨髓衰竭(BMF)和恶性肿瘤高发。FA镶嵌病是由造血细胞的逆转或其他补偿性突变引起的,可能与BMF逆转和血细胞对DNA破坏剂(破伤源)的敏感性降低有关;这种敏感性是FA的表型和诊断标志。关于FA镶嵌症的临床意义的不确定性仍然存在;在某些情况下,患者可以存活数十年而无BMF或血液系统恶性肿瘤;而在另一些情况下,尽管存在抗卡洛司汀耐药的细胞群,但仍发生血液学衰竭。由于临床评估通常基于淋巴细胞中的克拉斯蛋白酶抗性,因此镶嵌性的评估更加复杂,这可能是由于淋巴特异性谱系和更全能的造血干/祖细胞(HSPC)中的逆转事件引起的。在这篇综述中,我们描述了已发表的镶嵌术系列中的诊断方法和结果,包括血液计数正常化的相当大的间隔(1-6年),以及在骨髓祖细胞中显示出对克拉斯托原耐药的情况下相对有利的临床过程。我们还分析了已公布的FA镶嵌病例,重点是在确定血细胞计数正常化后的长期临床结局。FA镶嵌症中的血球计数正常化可能源于长期原始HSPC中的逆转事件,并且与BMF或血液系统恶性肿瘤的发生率低相关。这些观察结果对目前FA中的研究性治疗方案产生了影响,该方案旨在在长期重新繁殖的HSPC中进行基因校正。