# Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $199,999

## Abstract

PROJECT SUMMARY
As the initiating genetic events in tumorigenesis, germline variants in cancer predisposing genes perturb cell
growth and differentiation and set the stage for malignant transformation. Accordingly, the study of cancer
predisposing genes and their associated hereditary syndromes provides critical insights into normal physiology
and cancer biology. By investigating families with autosomal dominant transmission of thrombocytopenia and B-
acute lymphoblastic leukemia (B-ALL), we and others identified pathogenic germline variants affecting ETV6,
the gene encoding the ETS variant 6 transcriptional repressor. Subsequently, we sequenced germline samples
from 4,405 children with B-ALL and detected similar variants in 0.5% of patients. Further association studies
revealed a significant 22.94-fold enrichment of pathogenic ETV6 variants in this ALL cohort compared to 134,187
non-ALL controls in gnomAD (P= 2.2 × 10-16). These data firmly support our overall premise that pathogenic
germline ETV6 variants predispose to childhood ALL. To better understand how germline ETV6 variants
promote leukemogenesis, we used in vitro assays to interrogate their effects on the functions of the encoded
ETV6 protein. Notably, each of the pathogenic ETV6 variants examined significantly reduced ETV6 transcription
repressor activity, impaired ETV6 DNA binding capacity and mis-localized ETV6 to the cytoplasm. In parallel, we
generated a novel mouse model harboring a recurrent B-ALL-associated Etv6 variant (Etv6R355X). Preliminary
studies of Etv6R355X/+ mice reveal significant perturbations in early B cell development, as well as hematopoietic
stem and progenitor cell (HSPC) number and function. Finally, we generated isogenic induced pluripotent stem
cell (iPSC) lines harboring pathogenic ETV6 variants, which generate dysplastic megakaryocytes, similar to
ETV6 variant positive patients. Based on these results, we hypothesize that ETV6 variants predispose to
ALL by perturbing key transcriptional programs that impair hematopoietic development. In this proposal,
we will make use of our unique model systems to rigorously test this hypothesis. In Aim 1, we will characterize
the hematopoietic compartments of humans and mice that do or do not harbor pathogenic germline ETV6
variants. We will examine whether WT and ETV6 variant-positive iPSCs or mouse hematopoietic progenitors
properly differentiate along various lineages. To establish how germline ETV6 variants influence gene expression
in developing hematopoietic progenitors, in Aim 2 we will use RNA-sequencing and ATAC-sequencing to explore
transcriptional landscapes and identify putative ETV6 target genes in mouse and iPSC-derived B progenitors
and HSPC harboring WT or variant ETV6. Finally, in Aim 3 we will perform comprehensive whole genome and
RNA-sequencing of B-ALL samples to elucidate the somatic genetic lesions that function in concert with germline
ETV6 variants to drive B-leukemogenesis. We will use in vitro a...

## Key facts

- **NIH application ID:** 10247963
- **Project number:** 3R01CA241452-01A1S1
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** KIM Erika NICHOLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $199,999
- **Award type:** 3
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247963

## Citation

> US National Institutes of Health, RePORTER application 10247963, Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia (3R01CA241452-01A1S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10247963. Licensed CC0.

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