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TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells
June Li, … , Grover C. Bagby, Qishen Pang
June Li, … , Grover C. Bagby, Qishen Pang
Published October 25, 2007
Citation Information: J Clin Invest. 2007;117(11):3283-3295. https://doi.org/10.1172/JCI31772.
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Research Article Hematology Article has an altmetric score of 6

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

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Abstract

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-γ and TNF-α, 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-α in murine stem cells. TNF-α 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 WT mice, led to acute myelogenous leukemia. TNF-α induced ROS-dependent genetic instability in Fancc–/– but not in WT cells. The leukemic clones were TNF-α 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-α–induced clonal evolution. We conclude that TNF-α exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-α–hypersensitive Fancc–/– stem cells are purged.

Authors

June Li, Daniel P. Sejas, Xiaoling Zhang, Yuhui Qiu, Kalpana J. Nattamai, Reena Rani, Keaney R. Rathbun, Hartmut Geiger, David A. Williams, Grover C. Bagby, Qishen Pang

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Figure 1

TNF-α promotes clonal proliferation of TNF-α–resistant Fancc–/– BM progenitors.

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TNF-α promotes clonal proliferation of TNF-α–resistant Fancc–/– BM proge...
(A) TNF-α–mediated selection for resistant Fancc–/– BM cells. Lin-Sca-1+ BM cells from WT and Fancc–/– mice were cultured in complete medium containing IL-11, IL-6, Steel factor, and Flt-3 ligand and in the presence or absence of 10 ng/ml TNF-α. The total number of viable cells was counted by the trypan blue exclusion method at the times indicated. Result shown are representative of 5 separate experiments with similar results and expressed as mean of duplicates. (B) Colony growth assays demonstrated that while Fancc–/– BM progenitor cells were hypersensitive to TNF-α, the TNF-α–resistant Fancc–/– clonal progenitors were resistant in clonal assays. Data represent total number of colonies (mean ± SD) from 3 independent experiments. (C) Expression and activation of the TNF family signaling molecules in WT, freshly isolated Fancc–/–, and outgrown Fancc–/– BM progenitor cells. Cells were cultured in cytokine-supplemented medium in the absence or presence of 10 ng/ml TNF-α for 12 hours. RNA and protein extracts were prepared, and gene expression (right) and activation of caspase-3 and -8 were analyzed by RT-PCR and immunoblotting, respectively. (D) Spectral karyotype (SKY) analysis of the TNF-resistant cells demonstrated clonal cytogenetic abnormalities, including a clone with t(10;11) and another with t(4;9). The images shown were obtained from 1 culture. We conducted cytogenetic analysis on 3 different cultures, which gave some shared (e.g., the 10;11 translocations and monosomy 14) as well as different aberrations.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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