1022 – INHERITED BONE MARROW FAILURE AND GERMLINE PREDISPOSITION TO MYELOID NEOPLASIA: SOMATIC GENETIC REVERSION AND CLONAL ADAPTATION IN HEMATOPOIETIC STEM CELLS

IF 2.7 4区医学 Q2 HEMATOLOGY

Experimental hematology Pub Date : 2026-10-01 Epub Date: 2026-10-23 DOI:10.1016/j.exphem.2026.105517

Jörg Cammenga

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引用次数: 0

Abstract

Inherited bone marrow failure syndromes (IBMFS) and germline predisposition syndromes to myeloid neoplasms represent a group of hereditary disorders characterized by impaired hematopoiesis and an increased risk of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). These conditions are more common than previously appreciated, accounting for a significant proportion of childhood MDS and a subset of adult MDS/AML cases. IBMFS and germline predisposition syndromes result in decreased fitness of hematopoietic stem cells (HSCs), creating selective pressure for the acquisition of compensatory genetic alterations that may be either adaptive or maladaptive. Adaptive compensation restores HSC fitness toward normal levels, whereas maladaptive compensation promotes transformation to a myeloid neoplasm.

A remarkable feature of several IBMFS and germline predisposition syndromes is somatic genetic reversion, also termed “natural gene therapy.” This process occurs when a hematopoietic stem/progenitor cell acquires a secondary genetic event that mitigates or eliminates the effect of the inherited pathogenic variant. The reverted clone may gain a selective advantage and expand within the hematopoietic compartment, leading to improved blood counts and delayed disease progression.

The mechanisms of somatic genetic reversion are highly dependent on the mode of inheritance and the underlying biology of the respective IBMFS or predisposition syndrome. Somatic genetic reversion can be classified as either primary, affecting the same gene that causes the disease, or secondary, affecting a different gene whose alteration also results in increased cellular fitness.

This presentation provided an overview of the different IBMFS and germline predisposition syndromes associated with myeloid neoplasms, with a particular focus on the mechanisms of somatic genetic reversion and the insights they provide into HSC biology.

This presentation was made possible through a joint initiative of the International Society for Experimental Hematology (ISEH) and the European Hematology Association aimed at fostering collaborations between basic scientists and clinician-scientists in this area of hematology.

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遗传骨髓衰竭和种系对髓系肿瘤的易感性：造血干细胞的体细胞遗传逆转和克隆适应

遗传性骨髓衰竭综合征（IBMFS）和髓系肿瘤的种系易感综合征代表了一组以造血功能受损和骨髓增生异常综合征（MDS）和急性髓系白血病（AML）风险增加为特征的遗传性疾病。这些情况比以前认为的更常见，占儿童MDS和成人MDS/AML病例的很大比例。IBMFS和种系易感综合征导致造血干细胞（hsc）适应性下降，为获得适应性或不适应性的代偿性遗传改变产生选择性压力。适应性补偿使HSC恢复到正常水平，而不适应补偿则促进向髓系肿瘤的转变。一些IBMFS和种系易感性综合征的一个显著特征是体细胞遗传逆转，也被称为“自然基因治疗”。当造血干细胞/祖细胞获得次要遗传事件，减轻或消除遗传致病变异的影响时，就会发生这一过程。恢复的克隆可能获得选择性优势，并在造血室内扩张，导致血细胞计数改善和疾病进展延迟。体细胞遗传逆转的机制高度依赖于遗传模式和各自IBMFS或易感综合征的潜在生物学。体细胞遗传逆转可分为原发性，影响导致疾病的同一基因，或继发性，影响不同基因，其改变也导致细胞适应性增加。本报告概述了与髓系肿瘤相关的不同IBMFS和种系易感综合征，特别侧重于体细胞遗传逆转的机制及其对HSC生物学的见解。这次演讲是由国际实验血液学学会（ISEH）和欧洲血液学协会联合发起的，旨在促进基础科学家和临床科学家在血液学领域的合作。遗传性骨髓衰竭综合征（IBMFS）和髓系肿瘤的种系易感综合征代表了一组以造血功能受损和骨髓增生异常综合征（MDS）和急性髓系白血病（AML）风险增加为特征的遗传性疾病。这些情况比以前认为的更常见，占儿童MDS和成人MDS/AML病例的很大比例。IBMFS和种系易感综合征导致造血干细胞（hsc）适应性下降，为获得适应性或不适应性的代偿性遗传改变产生选择性压力。适应性补偿使HSC恢复到正常水平，而不适应补偿则促进向髓系肿瘤的转变。一些IBMFS和种系易感性综合征的一个显著特征是体细胞遗传逆转，也被称为“自然基因治疗”。当造血干细胞/祖细胞获得次要遗传事件，减轻或消除遗传致病变异的影响时，就会发生这一过程。恢复的克隆可能获得选择性优势，并在造血室内扩张，导致血细胞计数改善和疾病进展延迟。体细胞遗传逆转的机制高度依赖于遗传模式和各自IBMFS或易感综合征的潜在生物学。体细胞遗传逆转可分为原发性，影响导致疾病的同一基因，或继发性，影响不同基因，其改变也导致细胞适应性增加。本报告概述了与髓系肿瘤相关的不同IBMFS和种系易感综合征，特别侧重于体细胞遗传逆转的机制及其对HSC生物学的见解。这次演讲是由国际实验血液学学会（ISEH）和欧洲血液学协会联合发起的，旨在促进基础科学家和临床科学家在血液学领域的合作。

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来源期刊

Experimental hematology 医学-血液学

CiteScore

5.30

自引率

0.00%

发文量

审稿时长

58 days

期刊介绍： Experimental Hematology publishes new findings, methodologies, reviews and perspectives in all areas of hematology and immune cell formation on a monthly basis that may include Special Issues on particular topics of current interest. The overall goal is to report new insights into how normal blood cells are produced, how their production is normally regulated, mechanisms that contribute to hematological diseases and new approaches to their treatment. Specific topics may include relevant developmental and aging processes, stem cell biology, analyses of intrinsic and extrinsic regulatory mechanisms, in vitro behavior of primary cells, clonal tracking, molecular and omics analyses, metabolism, epigenetics, bioengineering approaches, studies in model organisms, novel clinical observations, transplantation biology and new therapeutic avenues.