From CHIP to Therapy-Related Myeloid Neoplasms: Biology, Risk, and Prevention

Clonal hematopoiesis of indeterminate potential (CHIP) is increasingly recognized as a precursor state that predisposes individuals to myeloid malignancies and adverse non-hematologic outcomes. In cancer survivors, prior exposure to cytotoxic chemotherapy and radiotherapy selects for and expands clones carrying mutations in genes governing DNA damage repair (e.g., TP53, PPM1D), epigenetic regulation (TET2, DNMT3A, ASXL1), and RNA splicing. This therapy-driven clonal evolution can culminate in therapy-related myeloid neoplasms (t-MNs), including therapy-related myelodysplastic syndromes, acute myeloid leukemia, and myelodysplastic/myeloproliferative overlap disorders, all of which carry a dismal prognosis and limited therapeutic options. As the cancer-survivor population grows, the continuum from CHIP to t-MN has become a clinical and biological priority. Despite recent advances, critical gaps remain in predicting which patients will progress and in deploying effective interception strategies.This Research Topic aims to consolidate current knowledge and stimulate new investigation into the molecular mechanisms, risk factors, and clinical trajectories linking CHIP to therapy-related myeloid neoplasms. Key questions include: How do defects in DNA damage repair pathways — including impaired homologous recombination, replication stress, and R-loop accumulation — cooperate with epigenetic and splicing-factor mutations to drive leukemic transformation after genotoxic therapy? What is the role of the bone marrow microenvironment, including niche-derived signaling (e.g., TGFβ, inflammatory cytokines), in shaping clonal fitness and treatment resistance? How can genomic profiling, sequential clonal monitoring, and integrated clinical models improve risk stratification before, during, and after cancer therapy? And critically, can emerging therapeutic strategies — such as PARP inhibitors exploiting synthetic lethality in DNA repair-deficient clones, targeted agents, or adapted treatment regimens — prevent or delay progression to overt t-MN? Recent advances in high-sensitivity sequencing, single-cell multi-omics, preclinical models of clonal selection under therapeutic stress, and early-phase clinical trials provide a timely foundation. By bridging basic, translational, and clinical perspectives, this collection seeks to accelerate actionable strategies that reduce the burden of therapy-related myeloid neoplasms.We welcome Original Research, Review, Mini Review, and Perspective articles on themes including, but not limited to:o DNA damage repair deficiency, replication stress, and synthetic lethality as drivers and therapeutic targets in CHIP and t-MNo The role of epigenetic (TET2, DNMT3A, ASXL1) and splicing-factor mutations in therapy-related clonal evolutiono Bone marrow microenvironment contributions to clonal selection, treatment resistance, and leukemic transformationo Genomic risk stratification and molecular classification of myeloid neoplasms arising after cytotoxic therapyo PARP inhibitors and other targeted agents in the prevention or treatment of t-MNo Preclinical models of therapy-related clonal hematopoiesis and myeloid transformationo Hematopoietic stem cell fitness, aging, and niche interactions under prior genotoxic exposureo Clinical outcomes and survivorship considerations in therapy-related myeloid neoplasmsPlease note: manuscripts consisting solely of bioinformatics or computational analysis of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) are out of scope for this section and will not be accepted as part of this Research Topic. Topic editors: Srinivas Chatla, Olga Weinberg, Anthony Hunter Source: https://www.frontiersin.org/research-topics/79460/from-chip-to-therapy-related-myeloid-neoplasms-biology-risk-and-prevention