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

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 6

H2O2-mediated Fancc–/– malignant transformation requires inhibition of apoptosis.

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H2O2-mediated Fancc–/– malignant transformation requires inhibition of a...
(A) BM progenitor cells isolated from WT or Fancc–/– mice were cultured in cytokine-supplemented medium in the absence or presence of the pan-caspase inhibitor Z-VAD-FMK (ZV-FMK; 100 μM) for 2 hours before H2O2 (10 μM) was added to the culture in each medium change. The cells were cultured for 30 days. The total number of viable cells was counted by the trypan blue exclusion method at the times indicated. Results were expressed as mean of duplicates. (B) Cells described in A were harvested on days 1 and 10 and analyzed for DNA strand breaks by the comet assay. The mean tail moment of WT control sample is expressed as 100%. Larger tail moments represent higher levels of DNA damage. Two cultures from each group were analyzed, and 50 cells per culture were scored from random sampling.