Proposed mechanism of clonal expansion and DNA damage accumulation in monosomy 7 cells. DNA damage from multiple environmental and intrinsic sources activates DNA damage response, resulting in a number of cellular responses, such as induction of cell-cycle arrest and repair of the lesions. In case of irreparable damage, cells undergo senescence or apoptosis. HSPCs are under an inflammatory microenvironment in BMF, resulting in dysregulated apoptosis signaling (this part of figure is adapted from Gañán-Gómez et al⁵⁵ ). The frequently overexpressed and/or constitutively activated transmembrane receptors (Fas, tumor necrosis factor [TNF] receptor 1 [TNFR1], TNFR2, Toll-like receptors [TLRs], and interferon-γ (IFN-γ) receptor [IFNGR]), their associated signal transducers, and recruited T cells induce apoptosis of HSCs through different signaling pathways. Dysregulated pathways or genes in monosomy 7 cells are highlighted in orange. Failure to repair DNA damage as well as impaired response to immune signaling in monosomy 7 cells might result in DNA damage accumulation and clonal expansion, and finally lead to leukemogenesis.