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This review consolidates new data on t-MN risk factors, focusing on clonal hematopoiesis, genetic predisposition, and abnormal microenvironmental signals. Improved mechanistic insight may enable preemptive screening, targeted intervention, and reduced future incidence.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & 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Factors, and Aberrant  \nMicroenvironment   \nDeepak Singhal1,2, Monika M. Kutyna1,2, 3, Christopher N. Hahn2,4, 5, Mithun Vinod Shah6, and Devendra K. Hiwase1,2, 3,4  \nTherapy-related myeloid neoplasm (t-MN), characterized by its association with  \nprior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy–induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment.  \nSignificance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis oft-MN may enable preemptive screening and even intervention in high-risk patients.  \nIntroductIon  \nCancer is the second leading cause of death worldwide, accounting for ∼ 9.6 million deaths in 2017 or nearly one in six deaths (1) . Though the incidence of cancers continues to increase, the risk of death from cancer has decreased by a third over the last 20 years, translating into 3.5 million averted cancer deaths. The long-term cancer survivorship, although celebrated, presents a new set of challenges for survivors and their caregivers. One of the emerging challenges is the increasing incidence of a second primary malignancy. This can  \n1Department of Haematology, Royal Adelaide Hospital, Central Adelaide Local Health Network, Adelaide, Australia. 2Adelaide Medical School, University of Adelaide, Adelaide, Australia. 3Precision Medicine Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, Australia. 4Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia. 5Genetics and Molecular Pathology, SA Pathology, Adelaide, Australia. 6Division of Hematology, Mayo Clinic, Rochester, Minnesota.  \nD. Singhal and M.M. Kutyna contributed equally to this article.  \noccur for a variety of reasons and includes a variety of cancer types, most commonly skin cancer. However, one of the most feared types of second primary cancer is therapy-related myeloid neoplasm (t-MN), which can present either as therapy-related acute myeloid leukemia (t-AML) or therapyrelated myelodysplastic syndrome (t-MDS) and, by definition, occurs in patients previously exposed to cytotoxic therapies (2, 3) . The prognosis of t-MN is universally dismal due to its aggressive nature and treatment refractoriness to conventional therapies, including stem cell transplantation (SCT) .  \nCorresponding Author: Devendra K. Hiwase, Royal Adelaide Hospital and South Australian Health and Medical Research Institute, Port Road, Adelaide, South Australia 5000, Australia. E-mail: [devendra.hiwase@sa.gov.au](devendra.hiwase@sa.gov.au)  \nBlood Cancer Discov 2024;5:400–16  \ndoi: 10. 1158/2643-3230 . BCD-24-0103  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.©2024 The Authors; Published by the American Association for Cancer Research  \nEncourag","cbCaiaA6w8soOuZ9","https://ap.wps.com/l/cbCaiaA6w8soOuZ9","pdf",6183835,17,"English","# Significance\n# Introduction\n# EpIdemiology","[{\"question\":\"What defines therapy-related myeloid neoplasms (t-MN)?\",\"answer\":\"t-MN is characterized by prior exposure to cytotoxic therapy and can present as therapy-related acute myeloid leukemia (t-AML) or therapy-related myelodysplastic syndrome (t-MDS).\"},{\"question\":\"Why are t-MN outcomes generally poor?\",\"answer\":\"The review describes universally dismal prognosis driven by aggressive disease biology and refractoriness to conventional therapies, including stem cell transplantation.\"},{\"question\":\"Which factors are highlighted as influencing t-MN risk?\",\"answer\":\"The document emphasizes interactions among clonal hematopoiesis, acquired and hereditary genetic predispositions, and an abnormal, senescent bone marrow microenvironment, alongside the types and intensity of cancer therapies received.\"}]","Therapy-Related Myeloid Neoplasms - Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment | PDF",1789999094,43]