The Contribution Of Toll-Like Receptor (Tlr) Pathway Hyper-Reactivity To Clonal Selection In Secondary Mds And Aml

Background: Stem cell (HSC) hypersensitivity to inflammatory cytokines and exaggerated TLR-dependent production of such cytokines contribute to bone marrow failure and clonal selection in Fanconi anemia (FA). Clonal neoplasms in FA patients and FA-deficient mice exhibit either resistance or paradoxical proliferative responses to tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN). Because FA MDS/AML shares cytogenetic and clinical features in common with secondary MDS/AML developing after prior MDS or exposure to cytotoxic chemotherapy (sMDS/sAML), we tested the idea that an FA-like TLR/cytokine hypersensitive phenotype might underlie clonal selection in sMDS/sAML. A pilot study of 4 hematologically normal individuals with histories of prior cytotoxic chemotherapy (including alkylating agents) revealed 2 whose committed progenitor cells were hypersensitive to TNF and IFN. Three patients with sMDS/sAML exhibited resistance to IFN and paradoxical growth responses to TNF. To determine the true prevalence of these FA-like phenotypes, we conducted a larger study of patients with sMDS/sAML, quantifying a) progenitor cell growth in response to inflammatory cytokines and b) TLR7/8 or TLR4-dependent cytokine production in peripheral blood monocytes.