Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment

Abstract

Summary Despite the inclusion of inherited myeloid malignancies as a separate entity in the World Health Organization Classification, many established predisposing loci continue to lack functional characterization. While germline mutations in the DNA repair factor ERCC excision repair 6 like 2 (ERCC6L2) give rise to bone marrow failure and acute myeloid leukaemia, their consequences on normal haematopoiesis remain unclear. To functionally characterise the dual impact of germline ERCC6L2 loss on human primary haematopoietic stem/progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs), we challenged ERCC6L2‐silenced and patient‐derived cells ex vivo. Here, we show for the first time that ERCC6L2‐deficiency in HSPCs significantly impedes their clonogenic potential and leads to delayed erythroid differentiation. This observation was confirmed by CIBERSORTx RNA‐sequencing deconvolution performed on ERCC6L2‐silenced erythroid‐committed cells, which demonstrated higher proportions of polychromatic erythroblasts and reduced orthochromatic erythroblasts versus controls. In parallel, we demonstrate that the consequences of ERCC6L2‐deficiency are not limited to HSPCs, as we observe a striking phenotype in patient‐derived and ERCC6L2‐silenced MSCs, which exhibit enhanced osteogenesis and suppressed adipogenesis. Altogether, our study introduces a valuable surrogate model to study the impact of inherited myeloid mutations and highlights the importance of accounting for the influence of germline mutations in HSPCs and their microenvironment.

ERCC6L2-related disease: a novel entity of bone marrow failure disorder with high risk of clonal evolution

“…Furthermore, this study included the first investigation into the consequences of ERCC6L2 alterations on the stromal niche, revealing in enhanced osteogenesis and suppressed adipogenesis [21]. This microenvironment resembles what was founded in sporadic cases of AML, suggesting the existence of a BM niche particularly prone to malignant transformations in ERCC6L2 mutated patients [22].…”

The Clinical Picture of the ERCC6L2 Disease - from Bone Marrow Failure to Acute Leukemia

“…The importance of the BM niche was advocated in a recent study using both patient samples and ERCC6L2-silenced cells which suggested that biallelic ERCC6L2 mutations also affect the mesenchymal stromal cells, which are paramount for fibrogenesis. 14 A prototype for somatic rescue is described in SAMD9/9L -mutated MDS with a nonrandom loss of chromosome seven, which was identified in 61% of the patients in a recent study. 25 Our data demonstrates that identifying somatically TP53-mutated clones at the initial presentation is essential.…”

“…Since the first depiction of patients with defective ERCC6L2, altogether 37 cases with biallelic germline ERCC6L2 variants have been described in the literature (including 14 patients from Finland). [1][2][3][10][11][12][13][14][15] In prior studies among Finnish patients, all cases have been homozygous for the variant ERCC6L2(NM_020207.7): c.1424delT (p.Ile475ThrfsTer36, rs768081343). 8,10 Moreover, a twenty-times-higher minor allele frequency of the variant in the Finnish population compared to the rest of the Europeans 16 suggests an accumulation of ERCC6L2 disease due to genetic drift as recognized in Finnish disease heritage (FDH).…”

Emerging bone marrow failure syndromes- new pieces to an unsolved puzzle

“…Upon treatment with radiotherapy, these patients showed a strikingly longer disease-free and overall survival than patients with wild-type ERCC6L2, indicating that ERCC6L2 loss may be clinically relevant (22). The most recent study described an impaired clonogenic capacity and erythroid differentiation in ERCC6L2-silenced HSPCs and a probable impact on mesenchymal stromal cells and their differentiation potential (23).…”

“…The overall penetrance is high with an estimate of 94% with two asymptomatic homozygotes still being very young (Table 1). Cytopenia and/or overt BMF develop early at an average age of 14 years and were reported in 24 out of 36 patients (66%, range 2 to 47 years (n=24), Table 1) (7,11,18,19,23,25,27,28). The development of hematologic malignancies (MDS/AML) has been described in approximately 31% of ERCC6L2 germlinemutated patients at an average age of 35 years (range 2-59 years (n=12), Table 1) (7,19,24,(28)(29)(30).…”