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-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 WT 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.

Cross talk between stimulated NF-κB and the tumor suppressor p53

“…Similar as in replicational stress, linking p53 to NF-kB signaling allows antiapoptotic gene expression in cells where the tumor suppressor can execute apoptosis if necessary. Such situations arise, for example, when TNF promotes inflammation-related tumorigenesis by NF-kB activation (Pikarsky et al, 2004;Hayashi et al, 2007) or by TNF-mediated induction of reactive oxygen species bearing mutagenic potential (Yan et al, 2006;Li et al, 2007;Yazdanpanah et al, 2009). Of note, p53-positive cells can protect themselves from such cyto-and genotoxic molecules by inducing MnSOD, an antioxidizing enzyme known to balance TNF signaling (Gilmore and Herscovitch, 2006).…”

Fancd2 −/− mice have hematopoietic defects that can be partially corrected by resveratrol

“…Because resveratrol may affect production of and/or hypersensitivity to proapoptotic cytokine TNF-␣ in the hematopoietic microenvironment, 14,38,39 we measured the levels of apoptosis in Fancd2 Ϫ/Ϫ and wild-type bone marrow cells. Annexin V and 7-aminoactinomycin D (7-AAD) staining revealed no significant gross increase in early apoptotic cells, defined as annexin V positive and 7-AAD negative, in Fancd2 Ϫ/Ϫ whole bone marrow cells, compared with wild-type controls.…”

“…10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, including…”

“…10-12 FA bone marrow cells (at least of the C complementation group) are also hypersensitive to these cytokines and undergo apoptosis when exposed to even low levels of them. [13][14][15] To better understand FA, multiple murine knockout models, includingand Fancl Ϫ/Ϫ mice, have been developed. 16 Notably, in contrast to humans with mutations of these genes, anemia has not been reported in any of these mice, although the bone marrow cells from the well-characterized Fancc Ϫ/Ϫ mice have shown reduced repopulating ability in transplantation experiments.…”

Therapeutically targeting SELF‐reinforcing leukemic niches in acute myeloid leukemia: A worthy endeavor?

“…It is well-known that MSCs actively participate in the "angiogenic switch" not only by releasing various angiogenic factors [62], but also by recruiting circulating vascular progenitor cells [63]. MSCs may inhibit adaptive and innate immunity by releasing immunosuppressive cytokines and effectors including tumor necrosis a (TNF-a) and interferon-g (IFN-g) either directly or under the influence of leukemic cells [64][65][66][67]. In addition, under the influence of Axl-expressing leukemic cells, BM derived MSCs are induced to express and produce the Axl ligand, i.e.…”