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There is growing evidence supporting an inherited basis for susceptibility to acute lymphoblastic leukemia (ALL) in children. In particular, we and others reported recurrent germline ETV6 variants linked to ALL risk, which collectively represent a novel leukemia predisposition syndrome. To understand the influence of ETV6 variation on ALL pathogenesis, we comprehensively characterized a cohort of 32 childhood leukemia cases arising from this rare syndrome. Of 34 nonsynonymous germline ETV6 variants in ALL, we identified 22 variants with impaired transcription repressor activity, loss of DNA binding, and altered nuclear localization. Missense variants retained dimerization with wild-type ETV6 with potentially dominant-negative effects. Whole-transcriptome and whole-genome sequencing of this cohort of leukemia cases revealed a profound influence of germline ETV6 variants on leukemia transcriptional landscape, with distinct ALL subsets invoking unique patterns of somatic cooperating mutations. 70% of ALL cases with damaging germline ETV6 variants exhibited hyperdiploid karyotype with characteristic recurrent mutations in NRAS, KRAS, and PTPN11. In contrast, the remaining 30% cases had a diploid leukemia genome and an exceedingly high frequency of somatic copy-number loss of PAX5 and ETV6, with a gene expression pattern that strikingly mirrored that of ALL with somatic ETV6-RUNX1 fusion. Two ETV6 germline variants gave rise to both acute myeloid leukemia and ALL, with lineage-specific genetic lesions in the leukemia genomes. ETV6 variants compromise its tumor suppressor activity in vitro with specific molecular targets identified by assay for transposase-accessible chromatin sequencing profiling. ETV6-mediated ALL predisposition exemplifies the intricate interactions between inherited and acquired genomic variations in leukemia pathogenesis.

Introduction: Historically, the majority of childhood cancers, including acute lymphoblastic leukemia (ALL), were not thought to have a hereditary basis. However, recent germline genomic studies have revealed that at least 5 - 10% of children with cancer (and approximately 3 - 4% of children with ALL) develop the disease due to an underlying genetic predisposition.Areas covered: This review discusses several recently identified ALL predisposing conditions and provides updates on other more well-established syndromes. It also covers topics related to the evaluation and management of children and family members at increased ALL risk.Expert opinion: Germline predisposition is gaining recognition as an important risk factor underlying the development of pediatric ALL. The challenge now lies in how best to capitalize on germline genetic information to improve ALL diagnosis, treatment, and perhaps even prevention.

The transcription factor ETV6 is required for bone marrow (BM) hematopoiesis and survival of adult hematopoietic stem cells (HSCs), but the mechanisms by which ETV6 regulates these processes remain unclear. We and others reported that germline variants in ETV6 are associated with autosomal dominant thrombocytopenia and occurrence of B-ALL. We identified likely pathogenic variants in 0.8% of 4,405 childhood ALL cases, and functional evaluation of these variants revealed impairment of transcriptional repression activity of ETV6. To investigate the impact of ETV6 variants on hematopoiesis, we generated a CRISPR-Cas9-derived mouse model (Etv6R355X/+) that mirrors an ETV6 R359X variant observed in multiple ALL cases. Flow cytometry of the BM revealed progressive changes in stem and progenitor cells, with 12-month-old ETV6R355X/+ mice showing ∼40% reductions in HSPCs and ∼40% increases in pro-B cells. Lineage-negative, cKit+, Sca1+ (LSK) cells from 3-month-old ETV6R355X/+ mice showed impaired engraftment in a competitive transplant model, as demonstrated by significantly reduced chimerism in primary, secondary, and tertiary recipients. To determine how the ETV6 R355X variant influences the hematopoietic transcriptional landscape, we performed RNA-seq and ATAC-seq from LSK and pro-B cells of 3-month-old WT or Etv6R355X/+ mice. We found 90 and 125 differentially expressed genes in LSK and pro-B cells, respectively. GSEA revealed enrichment of genes associated with hypoxia response and stem cell maintenance. ATAC-seq revealed a preferential shift toward an increase in open chromatin in Etv6R355X/+ cells within regions highly enriched for ETS DNA consensus motifs, indicating a potential loss of ETV6-mediated repression. These findings demonstrate that a pathogenic ETV6 variant can disrupt normal hematopoiesis and alter the transcriptional profile of stem and progenitor cells.