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Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia

Award Number: R01CA241452
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2020
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia - 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 Bacute 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 and in vivo approaches to assess the leukemiapromoting effects of these second hits. This project will provide new insights into the influence of germline genetic variation on hematopoiesis and development of B-ALL, the most common childhood cancer.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $211,268 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	4	4/1/2025	NON-COMPETING CONTINUATION	$211,268
														Subtotal = $211,268

Issue Date FY: 2024 ( Subtotal = $194,227 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	003	3	8/6/2024	NON-COMPETING CONTINUATION	$194,227
2024	2023	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	002	2	7/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$356,603
2024	2020	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	1	7/26/2024	SUPPLEMENT FOR EXPANSION	-$199,999
2024	2020	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	7/26/2024	NEW	-$156,604
														Subtotal = $194,227

Issue Date FY: 2023 ( Subtotal = $420,390 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	2	5/10/2023	EXTENSION WITH OR WITHOUT FUNDS	$420,390
														Subtotal = $420,390

Issue Date FY: 2020 ( Subtotal = $1,706,692 )
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	002	1	9/10/2020	SUPPLEMENT FOR EXPANSION	$199,999
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	001	1	7/9/2020	NEW	$962,336
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Treatment Research	000	1	3/24/2020	NEW	$544,357
2020	2020	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	003	1	9/15/2020	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,706,692

Grand Total All Awards = $2,532,577

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Pathogenesis of ETV6-Related Acute Lymphoblastic Leukemia

Award Number: R01CA241452

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2020

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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