Distinct clonal profiles in TBDs as markers of progressive marrow failure and clonal evolution. PGVs in telomere maintenance genes cause TBDs with very short telomeres and aberrant TP53 and IFN signaling pathway activation in HSPCs, ultimately triggering HSPC senescence and apoptosis, which leads to HSC exhaustion and BMF. The clonal landscape of TBD, a marker of progressive BMF, highlights that telomerase impairment and aberrant TP53 and INF upregulation are key constraints of HSC fitness. Chr1q⁺ and U2AF1^S34 and TP53 mutations are premalignant clonal events that increase the risk of developing hematologic malignancies mainly by suppressing TP53 pathway activation. U2AF1^S34 (but not U2AF1^Q157R mutations) and Chr1q⁺, initially compensatory and permissive of cell survival, were the main drivers of MDS/AML by ultimately allowing successive acquisition of preleukemic clonal events in other MDS-related genes. TP53 mutations were mostly associated with evolution to AML due to TP53 biallelic inactivation; these mutations are also associated with solid cancers. In contrast, PPM1D, POT1, and TERTp mutations are compensatory events that do not increase the risk of cancer development. Somatic POT1 and TERTp mutations likely overcome restricted HSC cell fitness caused by germ line TBD mutations by modulating telomerase activity and increasing cell proliferation. PPM1D mutations did not correlate with previous exposure to chemotherapies and may enhance HSCs’ competitive fitness and suppress the DNA damage response by TP53-negative regulation. The compensatory effects of these somatic mutations on hematopoiesis (eg, telomere lengthening or improved PB counts) may be limited by these mutations’ low clonal burden at the time of detection. INF, interferon; LoF, loss-of-function.