title: TNF-alpha 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.
authors.affiliation: Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.
authors.forename: June
authors.initials: J
authors.lastname: Li
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Sejas
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuhui
authors.initials: Y
authors.lastname: Qiu
authors.forename: Kalpana J
authors.initials: KJ
authors.lastname: Nattamai
authors.forename: Reena
authors.initials: R
authors.lastname: Rani
authors.forename: Keaney R
authors.initials: KR
authors.lastname: Rathbun
authors.forename: Hartmut
authors.initials: H
authors.lastname: Geiger
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002869:Chromosome Aberrations; D005199:Fanconi Anemia / Q000235:genetics / Q000276:immunology*; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics / Q000276:immunology*; D005816:Genetic Complementation Test; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D033581:Stem Cell Transplantation; D015996:Survival Rate; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases