Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Nat Commun. 2021 Feb 26;12(1):1334. doi: 10.1038/s41467-021-21588-4.
To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
为了理解介导生殖系遗传白血病易感性的机制，我们研究了遗传核糖体病 Shwachman-Diamond 综合征（SDS），这是一种骨髓衰竭疾病，早年患髓系恶性肿瘤的风险很高。为了明确 SDS 中克隆性造血的机制基础，我们对接受 SDS 治疗的患者进行了纵向研究，以发现其获得的体细胞突变。在此，我们报告称，多个独立的造血克隆在生命早期出现，最常见的是携带 EIF6 或 TP53 的杂合突变。我们表明，生殖系 SBDS 缺陷会造成适应性限制，通过两种不同的机制驱动体细胞克隆的选择，从而产生不同的临床后果。EIF6 失活通过改善潜在的 SDS 核糖体缺陷并增强克隆适应性，介导具有有限白血病潜能的代偿途径。TP53 突变通过失活肿瘤抑制检查点而不纠正核糖体缺陷来定义具有增强白血病潜能的失调途径。随后白血病的发展与获得双等位 TP53 改变有关。这些结果从机制上把白血病易感性与细胞适应性的种系遗传限制联系起来，并为临床监测策略提供了合理的框架。
