TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells

被引：115

作者：

Li, June

Sejas, Daniel P.

Zhang, Xiaoling

Qiu, Yuhui

Nattamai, Kalpana J.

Rani, Reena

Rathbun, Keaney R.

Geiger, Hartmut

Williams, David A.

Bagby, Grover C. ^{[1
]}

Pang, Qishen

机构：

[1] Childrens Hosp, Med Ctr, Div Expt Hematol, Cincinnati, OH 45229 USA

[2] Oregon Hlth & Sci Univ, Sch Med, OHSU Canc Inst, Portland, OR 97201 USA

[3] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH USA

[4] Portland VA Med Ctr, Portland, OR USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2007年 / 117卷 / 11期

关键词：

D O I：

10.1172/JCI31772

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

The molecular pathogenesis of the myeloid leukemias that frequently occur in patients with Fanconi anemia (FA) is not well defined. Hematopoietic stem cells bearing inactivating mutations of FA complementation group C (FANCC) are genetically unstable and hypersensitive to apoptotic cytokine cues including IFN-gamma and TNF-alpha, but neoplastic stem cell clones that arise frequently in vivo are resistant to these cytokines. Reasoning that the combination of genetic instability and cytokine hypersensitivity might create an environment supporting the emergence of leukemic stem cells, we tested the leukemia-promoting effects of TNF-alpha in murine stem cells. TNF-alpha exposure initially profoundly inhibited the growth of Fancc(-/-) stem cells. However, longer-term exposure of these cells promoted the outgrowth of cytogenetically abnormal clones that, upon transplantation into congenic V/T mice, led to acute myelogenous leukemia. TNF-alpha. induced ROS-dependent genetic instability in Fancc(-/-) but not in WT cells. The leukemic clones were TNF-alpha resistant but retained their characteristic hypersensitivity to mitomycin C and exhibited high levels of chromosomal instability. Expression of FANCC cDNA in Fancc(-/-) stem cells protected them from TNF-alpha-induced clonal. evolution. We conclude that TNF-alpha exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-alpha-hypersensitive Fancc(-/-) stem cells are purged.

引用

页码：3283 / 3295

页数：13

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