Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene
Suppression of apoptosis in hematopoietic factor-dependent progenitor cell lines by expression of the FAC gene
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DOI：
10.1182/blood.v88.12.4558.bloodjournal88124558
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发表时间：
1996-12-15
期刊：
影响因子：
20.3
通讯作者：
Buchwald, M
中科院分区：
文献类型：
--
作者：
Cumming, RC;Liu, JM;Buchwald, M
范可尼贫血（FA）是一种遗传异质性的遗传性血液疾病，其特征是骨髓衰竭、先天畸形和易患白血病。由于FA细胞对DNA交联剂高度敏感，且具有染色体不稳定性，因此FA被认为是一种DNA修复障碍，但FA细胞中确切的细胞缺陷尚未确定。对C组患者（FAC）缺陷基因的序列分析显示与其他已知基因没有显着同源性。FAC蛋白定位于细胞质，表明FAC可能在DMA修复中起间接作用或参与不同的细胞途径。最近的证据表明，FA细胞可能倾向于凋亡，特别是在用DNA交联剂处理后。基因可以抑制细胞凋亡的证明已经通过在生长因子依赖性细胞系中过表达这些基因来完成，这些细胞系在因子撤除后因细胞凋亡而死亡。使用逆转录病毒介导的基因转移，我们提出的证据表明，FAC在造血因子依赖的祖细胞系32 D和MO 7 e的表达可以抑制生长因子撤除诱导的细胞凋亡。碘化丙啶染色细胞的流式细胞术和形态学分析显示，生长因子剥夺后，FAC-retroviral转导的细胞凋亡水平显著降低。FAC在两种细胞系中的表达促进了活力的增加而不是增殖，这与其他凋亡抑制基因如Bcl-2一致。这些发现意味着，FAC可能作为一个介质的凋亡途径启动生长因子撤退。此外，先天性畸形和血液学异常的特点FA可能与增加的倾向FA祖细胞进行凋亡，特别是在细胞外信号的情况下。(C)1996年，美国血液学会。
Fanconi anemia (FA) is a genetically heterogeneous, inherited blood disorder characterized by bone marrow failure, congenital malformations, and a predisposition to leukemias. Because FA cells are hypersensitive to DNA cross-linking agents and have chromosomal instability, FA has been viewed as a disorder of DNA repair, However, the exact cellular defect in FA cells has not been identified. Sequence analysis of the gene defective in group C patients (FAC) has shown no significant homologies to other known genes. The FAC protein has been localized to the cytoplasm, indicating that FAC may either play an indirect role in DMA repair or is involved in a different cellular pathway. Recent evidence has indicated that FA cells may be predisposed to apoptosis, especially after treatment with DNA cross-linking agents. The demonstration that genes can suppress apoptosis has been accomplished by overexpression of such genes in growth factor-dependent cell lines that die by apoptosis after factor withdrawal. Using retroviral-mediated gene transfer, we present evidence that expression of FAC in the hematopoietic factor-dependent progenitor cell lines 32D and MO7e can suppress apoptosis induced by growth factor withdrawal. Flow cytometry and morphologic analysis of propidium iodide stained cells showed significantly lower levels of apoptosis in FAC-retroviral transduced cells after growth factor deprivation. Expression of FAC in both cell lines promoted increased viability rather than proliferation, which is consistent with other apoptosis-inhibiting genes such as Bcl-2. These findings imply that FAC may act as a mediator of an apoptotic pathway initiated by growth factor withdrawal. Furthermore, the congenital malformations and hematologic abnormalities characterizing FA may be related to an increased predisposition of FA progenitor cells to undergo apoptosis, particularly in the absence of extracellular signals. (C) 1996 by The American Society of Hematology.