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Leukemia. 2019 Jul;33(7):1773-1782. doi: 10.1038/s41375-019-0385-0. Epub 2019 Jan 29.

A germline HLTF mutation in familial MDS induces DNA damage accumulation through impaired PCNA polyubiquitination.

Author information

1
Department of Hematology and Oncology, The University of Tokyo, Tokyo, Japan.
2
Department of Medical Genomics, The University of Tokyo, Tokyo, Japan.
3
Department of Cellular Signaling, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
4
Department of Hematology, Tokyo Medical Center, Tokyo, Japan.
5
Department of Hematology, Japanese Red Cross Medical Center, Tokyo, Japan.
6
School of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
7
Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan.
8
Department of Hematology/Oncology, Gunma Children's Medical Center, Gunma, Japan.
9
National Cancer Center Research Institute, Tokyo, Japan.
10
Department of Hematology and Oncology, The University of Tokyo, Tokyo, Japan. kurokawa-tky@umin.ac.jp.

Abstract

Although several causal genes of familial myelodysplastic syndromes (MDS) have been identified, the genetic landscape and the molecular pathogenesis are not totally understood. To explore novel driver genes and their pathogenetic significance, we performed whole-exome sequence analysis of four individuals from a familial MDS pedigree and 10 candidate single-nucleotide variants (C9orf43, CYP7B1, EFHB, ENTPD7, FAM160B2, HELZ2, HLTF, INPP5J, ITPKB, and RYK) were identified. Knockdown screening revealed that Hltf downregulation enhanced colony-forming capacity of primary murine bone marrow (BM) stem/progenitor cells. γH2AX immunofluorescent staining assay revealed increased DNA damage in a human acute myeloid leukemia (AML) cell line ectopically expressing HLTF E259K, which was not observed in cells expressing wild-type HLTF. Silencing of HLTF in human AML cells also led to DNA damage, indicating that HLTF E259K is a loss-of-function mutation. Molecularly, we found that an E259K mutation reduced the binding capacity of HLTF with ubiquitin-conjugating enzymes, methanesulfonate sensitive 2 and ubiquitin-conjugating enzyme E2N, resulting in impaired polyubiquitination of proliferating cell nuclear antigen (PCNA) in HLTF E259K-transduced cells. In summary, our results indicate that a familial MDS-associated HLTF E259K germline mutation induces accumulation of DNA double-strand breaks, possibly through impaired PCNA polyubiquitination.

PMID:
30696947
DOI:
10.1038/s41375-019-0385-0

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