Kato Hisaya, Maezawa Yoshiro, Nishijima Dai, Iwamoto Eisuke, Takeda June, Kanamori Takashi, Yamaga Masaya, Mishina Tatsuzo, Takeda Yusuke, Izumi Shintaro, Hino Yutaro, Nishi Hiroyuki, Ishiko Jun, Takeuchi Masahiro, Kaneko Hiyori, Koshizaka Masaya, Mimura Naoya, Kuzuya Masafumi, Sakaida Emiko, Takemoto Minoru, Shiraishi Yuichi, Miyano Satoru, Ogawa Seishi, Iwama Atsushi, Sanada Masashi, Yokote Koutaro
Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
Department of Advanced Diagnosis, Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.
Exp Hematol. 2022 May;109:11-17. doi: 10.1016/j.exphem.2022.02.005. Epub 2022 Feb 28.
Werner syndrome (WS) is a progeroid syndrome caused by mutations in the WRN gene, which encodes the RecQ type DNA helicase for the unwinding of unusual DNA structures and is implicated in DNA replication, DNA repair, and telomere maintenance. patients with WS are prone to develop malignant neoplasms, including hematological malignancies. However, the pathogenesis of WS-associated hematological malignancies remains uncharacterized. Here we investigated the somatic gene mutations in WS-associated myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). Whole-exome sequencing (WES) of 4 patients with WS with MDS/AML revealed that all patients had somatic mutations in TP53 but no other recurrent mutations in MDS/AML. TP53 mutations were identified at low allele frequencies at more than one year before the MDS/AML stage. All 4 patients had complex chromosomal abnormalities including those that involved TP53. Targeted sequencing of nine patients with WS without apparent blood abnormalities did not detect recurrent mutations in MDS/AML except for a PPM1D mutation. These results suggest that patients with WS are apt to acquire TP53 mutations and/or chromosomal abnormalities involving TP53, rather than other MDS/AML-related mutations. TP53 mutations are frequently associated with prior exposure to chemotherapy; however, all four patients with WS with TP53 mutations/deletions had not received any prior chemotherapy, suggesting a pathogenic link between WRN mutations and p53 insufficiency. These results indicate that WS hematopoietic stem cells with WRN insufficiency acquire competitive fitness by inactivating p53, which may cause complex chromosomal abnormalities and the subsequent development of myeloid malignancies. These findings promote our understanding of the pathogenesis of myeloid malignancies associated with progeria.
沃纳综合征（WS）是一种早老性综合征，由WRN基因突变引起，该基因编码RecQ型DNA解旋酶，用于解开异常DNA结构，并参与DNA复制、DNA修复和端粒维持。WS患者容易发生恶性肿瘤，包括血液系统恶性肿瘤。然而，WS相关血液系统恶性肿瘤的发病机制仍不清楚。在这里，我们研究了WS相关骨髓增生异常综合征/急性髓系白血病（MDS/AML）中的体细胞基因突变。对4例患有MDS/AML的WS患者进行全外显子测序（WES）发现，所有患者均有TP53体细胞突变，但在MDS/AML中无其他复发性突变。在MDS/AML阶段前一年多，TP53突变以低等位基因频率被识别。所有4例患者均有复杂的染色体异常，包括涉及TP53的异常。对9例无明显血液异常的WS患者进行靶向测序，除PPM1D突变外，未检测到MDS/AML中的复发性突变。这些结果表明，WS患者易于获得TP53突变和/或涉及TP53的染色体异常，而非其他与MDS/AML相关的突变。TP53突变常与先前接触化疗有关；然而，所有4例有TP53突变/缺失的WS患者均未接受过任何先前的化疗，这表明WRN突变与p53功能不全之间存在致病联系。这些结果表明，具有WRN功能不全的WS造血干细胞通过使p53失活获得竞争适应性，这可能导致复杂的染色体异常和随后髓系恶性肿瘤的发生。这些发现促进了我们对与早衰相关的髓系恶性肿瘤发病机制的理解。
