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

Abstract

ERCC excision repair 6 like 2 (ERCC6L2) gene encodes for different helicase-like protein members of the Snf2 family involved in transcription-coupled nucleotide excision repair and in cell proliferation. Germline homozygous mutations in children and adults predispose to a peculiar bone marrow failure phenotype characterized by mild hematological alterations with a high risk of developing acute myeloid leukemia. The outcome for patients with leukemia progression is dismal while patients undergoing hematopoietic stem cell transplantation in the early stage have better outcomes. The ERCC6L2-related hematological disease presents a high penetrance, posing important questions regarding the treatment strategies and possible preemptive approaches. This review describes the biological function of ERCC6L2 and the clinical manifestations of the associated disease, trying to focus on the unsolved clinical questions.

Human leucocyte antigen‐matched related haematopoietic stem cell transplantation using low‐dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia

“…Pathogenic mutations in ERCC6L2 are associated with defects in DNA repair and lead to IBMFS with a high risk of MDS/AML 34–36 . An optimal conditioning regimen for ERCC6L2 ‐associated BM failure needs to be defined.…”

“…Pathogenic mutations in ERCC6L2 are associated with defects in DNA repair and lead to IBMFS with a high risk of MDS/AML. [34][35][36] An optimal conditioning regimen for ERCC6L2-associated BM failure needs to be defined. Our first patient had increasing cytopenia with myelodysplastic features within a few months of transplant and ultimately progressed to refractory AML, despite receiving a second transplant.…”

Protein structural context of cancer mutations reveals molecular mechanisms and identifies novel candidate driver genes

“…It also possesses two domains that commonly occur in known TSGs: the Helicase_C domain is found in nine well-established TSGs, and the SNF2-rel_dom domain is found in three. Notably, patients with bone-marrow-failure syndrome have also been observed to be at a high risk of developing acute myeloid leukemia 57 . Thus, ERCC6L2 seems to be a strong candidate as a putative tumour suppressor.…”

An atypical patient with bone marrow failure syndrome‐2 without microcephaly and learning disability in a Chinese family

“…[3][4][5] In all, 31 cases of homozygous germline ERCC6L2 mutation-related diseases have been reported, mostly in individuals showing manifestations of bone marrow failure and relatively high penetrance. 6 Allogeneic haematopoietic stem cell transplantation (Allo-HSCT) remains the only curative measure for IBMFS but possibly increases the malignant transformation risk. 7 Moreover, somatic abnormalities or other non-hematological alterations already present are irreversible.…”

“…IBMFS patients carrying germline mutations have an increased risk of transformation to myelodysplastic syndrome and acute myeloid leukaemia, 14 while the early administration of allo-HSCT in patients with ERCC6L2-associated IBMFS might obtain better outcomes. 6 Consequently, dynamic monitoring of blood counts and bone marrow haematopoiesis assists in detecting early transformation and making timely clinical interventions. Our case report with heterogeneous phenotypes with previous cases expanded the genotype and phenotype of BMFS2 across different ethnic populations.…”