Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Curr Hematol Malig Rep. 2022 Jun;17(3):61-68. doi: 10.1007/s11899-022-00662-8. Epub 2022 May 7.
Telomere biology disorders (TBDs) are cancer-predisposing multisystemic diseases that portend a higher risk of transforming into myeloid neoplasms (MNs). Due to the rarity and high variability of clinical presentations, TBD-specific characteristics of MN and the mechanisms behind this predisposition are not well defined. Herein, we review recent studies on TBD patient cohorts describing myeloid transformation events and summarize efforts to develop screening and treatment guidelines for these patients.
Preliminary studies have indicated that TBD patients have a higher prevalence of somatic genetic alterations in hematopoietic cells, an age-related phenomenon, also known as clonal hematopoiesis; increasing predisposition to MN. The CH mutational landscape in TBD differs from that observed in non-TBD patients and preliminary data suggest a higher frequency of somatic mutations in the DNA repair mechanism pathway. Although initial studies did not observe specific features of MN in TBD patients, certain events are common in TBD, such as hypocellular bone marrows. The mechanisms of MN development need further elucidation. Current management options for MN-TBD patients need to be individualized and tailored as per the clinical context. Because of the high sensitivity to alkylator chemotherapy and radiation conferred by short telomeres, non-cytotoxic targeted therapies and immunotherapy are ideal therapeutic options, but these therapies are still being tested in clinical trials. Defining the mechanisms of CH evolution in TBD and identifying risk factors leading to MN evolution will allow for the development of screening and treatment guidelines for these patients.
端粒生物学障碍（TBD）是一种易诱发癌症的多系统疾病，预示着向髓系肿瘤（MN）转化的风险更高。由于临床表现的罕见性和高度可变性，TBD 特异性 MN 特征及其倾向背后的机制尚未明确。本文综述了最近关于描述骨髓转化事件的 TBD 患者队列的研究，并总结了为这些患者制定筛查和治疗指南的努力。
初步研究表明，TBD 患者造血细胞中存在更高频率的体细胞遗传改变，这是一种与年龄相关的现象，也称为克隆性造血；增加了向 MN 转化的倾向。TBD 中的 CH 突变景观与非 TBD 患者观察到的不同，初步数据表明，DNA 修复机制途径中的体细胞突变频率更高。尽管最初的研究并未在 TBD 患者中观察到 MN 的特定特征，但某些事件在 TBD 中很常见，例如骨髓细胞减少。MN 发展的机制需要进一步阐明。MN-TBD 患者的当前管理选择需要根据临床情况进行个体化和定制。由于短端粒赋予了对烷化剂化疗和放疗的高度敏感性，非细胞毒性靶向治疗和免疫疗法是理想的治疗选择，但这些疗法仍在临床试验中进行测试。明确 TBD 中 CH 进化的机制并确定导致 MN 进化的风险因素将为这些患者制定筛查和治疗指南。
