The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia

Marja Hakkarainen, Ilse Kaaja, Suvi P.M. Douglas, Tom Vulliamy, Inderjeet Dokal, Jean Soulier, Lise Larcher, Régis Peffault de Latour, Thierry Leblanc, Flore Sicre de Fontbrune, Timo Siitonen, Olli Lohi, Eva Hellström-Lindberg, Gisela Barbany, Bianca Tesi, Akiko Shimamura, Fabian Beier, Sharon Jackson, Amir Asher Kuperman, Tzipora Falik ZaccaiHannah Tamary, Cristina Mecucci, Ilaria Capolsini, Kirsi Jahnukainen, Urpu Salmenniemi, Riitta Niinimäki, Teppo Varilo, Outi Kilpivaara, Ulla Wartiovaara-Kautto

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Biallelic germ line excision repair cross-complementing 6 like 2 (ERCC6L2) variants strongly predispose to bone marrow failure (BMF) and myeloid malignancies, characterized by somatic TP53-mutated clones and erythroid predominance. We present a series of 52 subjects (35 families) with ERCC6L2 biallelic germ line variants collected retrospectively from 11 centers globally, with a follow-up of 1165 person-years. At initial investigations, 32 individuals were diagnosed with BMF and 15 with a hematological malignancy (HM). The subjects presented with 19 different variants of ERCC6L2, and we identified a founder mutation, c.1424delT, in Finnish patients. The median age of the subjects at baseline was 18 years (range, 2-65 years). Changes in the complete blood count were mild despite severe bone marrow (BM) hypoplasia and somatic TP53 mutations, with no significant difference between subjects with or without HMs. Signs of progressive disease included increasing TP53 variant allele frequency, dysplasia in megakaryocytes and/or erythroid lineage, and erythroid predominance in the BM morphology. The median age at the onset of HM was 37.0 years (95% CI, 31.5-42.5; range, 12-65 years). The overall survival (OS) at 3 years was 95% (95% CI, 85-100) and 19% (95% CI, 0-39) for patients with BMF and HM, respectively. Patients with myelodysplastic syndrome or acute myeloid leukemia with mutated TP53 undergoing hematopoietic stem cell transplantation had a poor outcome with a 3-year OS of 28% (95% CI, 0-61). Our results demonstrated the importance of early recognition and active surveillance in patients with biallelic germ line ERCC6L2 variants.

Original languageEnglish
Pages (from-to)2853-2866
Number of pages14
Issue number23
Early online date23 Mar 2023
StatePublished - 8 Jun 2023

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© 2023 The American Society of Hematology


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