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

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

    Research output: Contribution to journalArticle

    94 Citations (Scopus)

    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.

    Original languageEnglish (US)
    Pages (from-to)3283-3295
    Number of pages13
    JournalJournal of Clinical Investigation
    Volume117
    Issue number11
    DOIs
    StatePublished - Nov 1 2007

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    Clonal Evolution
    Fanconi Anemia
    Stem Cells
    Clone Cells
    Cytokines
    Hypersensitivity
    Congenic Mice
    Chromosomal Instability
    Myeloid Leukemia
    Neoplastic Stem Cells
    Mitomycin
    Hematopoietic Stem Cells
    Acute Myeloid Leukemia
    Cues
    Leukemia
    Complementary DNA
    Transplantation
    Mutation
    Growth

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Li, J., Sejas, D. P., Zhang, X., Qiu, Y., Nattamai, K. J., Rani, R., ... Pang, Q. (2007). TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. Journal of Clinical Investigation, 117(11), 3283-3295. https://doi.org/10.1172/JCI31772

    TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. / Li, June; Sejas, Daniel P.; Zhang, Xiaoling; Qiu, Yuhui; Nattamai, Kalpana J.; Rani, Reena; Rathbun, Keaney R.; Geiger, Hartmut; Williams, David A.; Bagby, Grover C.; Pang, Qishen.

    In: Journal of Clinical Investigation, Vol. 117, No. 11, 01.11.2007, p. 3283-3295.

    Research output: Contribution to journalArticle

    Li, J, Sejas, DP, Zhang, X, Qiu, Y, Nattamai, KJ, Rani, R, Rathbun, KR, Geiger, H, Williams, DA, Bagby, GC & Pang, Q 2007, 'TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells', Journal of Clinical Investigation, vol. 117, no. 11, pp. 3283-3295. https://doi.org/10.1172/JCI31772
    Li, June ; Sejas, Daniel P. ; Zhang, Xiaoling ; Qiu, Yuhui ; Nattamai, Kalpana J. ; Rani, Reena ; Rathbun, Keaney R. ; Geiger, Hartmut ; Williams, David A. ; Bagby, Grover C. ; Pang, Qishen. / TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 11. pp. 3283-3295.
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