A high prevalence of myeloid malignancies in progeria with Werner syndrome is associated with p53 insufficiency.

Abstract

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.

• Authors: Hisaya Kato, Yoshiro Maezawa, Dai Nishijima, Eisuke Iwamoto, June Takeda, Takashi Kanamori, Masaya Yamaga, Tatsuzo Mishina, Yusuke Takeda, Shintaro Izumi, Yutaro Hino, Hiroyuki Nishi, Jun Ishiko, Masahiro Takeuchi, Hiyori Kaneko, Masaya Koshizaka, Naoya Mimura, Masafumi Kuzuya, Emiko Sakaida, Minoru Takemoto, Yuichi Shiraishi, Satoru Miyano, Seishi Ogawa, Atsushi Iwama, Masashi Sanada, Koutaro Yokote
• Journal: Experimental hematology (Exp Hematol) Vol. 109 Pg. 11-17 (05 2022) ISSN: 1873-2399 [Electronic] Netherlands
• PMID: 35240258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

Chemical References

• Tumor Suppressor Protein p53

Topics

• Chromosome Aberrations
• Hematologic Neoplasms
• Humans
• Leukemia, Myeloid, Acute (genetics, pathology)
• Mutation
• Myeloproliferative Disorders
• Prevalence
• Progeria (genetics)
• Tumor Suppressor Protein p53 (genetics)
• Werner Syndrome (complications, genetics)