Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 117, Issue 11, Pages 3283-3295Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI31772
Keywords
-
Categories
Funding
- NCI NIH HHS [R01 CA109641] Funding Source: Medline
- NCRR NIH HHS [M01 RR000334] Funding Source: Medline
- NHLBI NIH HHS [P01 HL048546, R01 HL076712] Funding Source: Medline
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available