Si Yue, Ciccone Samantha, Yang Feng-Chun, Yuan Jin, Zeng Daisy, Chen Shi, van de Vrugt Henri J, Critser John, Arwert Fre, Haneline Laura S, Clapp D Wade
Department of Microbiology and Immunology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, USA.
Blood. 2006 Dec 15;108(13):4283-7. doi: 10.1182/blood-2006-03-007997. Epub 2006 Aug 31.
Fanconi anemia (FA) is a heterogeneous genetic disorder characterized by bone marrow (BM) failure and cancer susceptibility. Identification of the cDNAs of FA complementation types allows the potential of using gene transfer technology to introduce functional cDNAs as transgenes into autologous stem cells and provide a cure for the BM failure in FA patients. However, strategies to enhance the mobilization, transduction, and engraftment of exogenous stem cells are required to optimize efficacy prior to widespread clinical use. Hypersensitivity of Fancc-/- cells to interferon-gamma (IFN-gamma), a nongenotoxic immune-regulatory cytokine, enhances engraftment of syngeneic wild-type (WT) cells in Fancc-/- mice. However, whether this phenotype is of broad relevance in other FA complementation groups is unresolved. Here we show that primitive and mature myeloid progenitors in Fanca-/- and Fancg-/- mice are hypersensitive to IFN-gamma and that in vivo infusion of IFN-gamma at clinically relevant concentrations was sufficient to allow consistent long-term engraftment of isogenic WT repopulating stem cells. Given that FANCA, FANCC, and FANCG complementation groups account for more than 90% of all FA patients, these data provide evidence that IFN-gamma conditioning may be a useful nongenotoxic strategy for myelopreparation in FA patients.
范可尼贫血（FA）是一种异质性遗传疾病，其特征为骨髓（BM）衰竭和癌症易感性。鉴定FA互补型的cDNA使得利用基因转移技术将功能性cDNA作为转基因导入自体干细胞并治愈FA患者的BM衰竭成为可能。然而，在广泛临床应用之前，需要采取策略来增强外源性干细胞的动员、转导和植入，以优化疗效。Fancc-/-细胞对干扰素-γ（IFN-γ）（一种非基因毒性免疫调节细胞因子）超敏，可增强同基因野生型（WT）细胞在Fancc-/-小鼠中的植入。然而，这种表型在其他FA互补组中是否具有广泛相关性仍未解决。在此，我们表明Fanca-/-和Fancg-/-小鼠中的原始和成熟髓系祖细胞对IFN-γ超敏，并且以临床相关浓度在体内输注IFN-γ足以使同基因WT再填充干细胞持续长期植入。鉴于FANCA、FANCC和FANCG互补组占所有FA患者的90%以上，这些数据提供了证据，表明IFN-γ预处理可能是一种用于FA患者骨髓预处理的有用的非基因毒性策略。
