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Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors

Award Number: R01NS116421
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors - Project Abstract Individuals with neurofibromatosis type 1 (NF1) have an approximately 160-fold increased risk of developing malignant peripheral nerve sheath tumor (MPNST). As a leading cause of death for NF1 patients. MPNST has no effective therapy and thus there is an urgent need for new therapies. The dramatically increased risk of developing MPNSTs is caused by the presence of plexiform neurofibromas (PNFs), the major benign precursor lesion for NF1-MPNST. It has been proposed that PNFs are congenital lesions, arising from the early stages of nerve development when neural-crest stem cells differentiate into Schwann cell (SC) lineages, which give rise to either myelinating or nonmyelinating SCs (mSCs or nmSCs). In the normal nerve, unmyelinated axons are sorted and ensheathed by nmSCs into individual pockets, forming Remak bundles. Whereas no defect in SC precursors or mSCs was observed, Nf1 loss (Nf1-/-) during early nerve development induced a pocket defect in Remak bundles, characterized by abnormally sorted unmyelinated axons. These abnormal Remak pockets progress to a stage with axonal degeneration and abnormal proliferation of dissociated SCs, leading to the formation of PNFs. Axonal degeneration may contribute to PNF formation by inducing a nerve injury environment, a concept supported by the observation that Nf1 loss in mature SCs is not sufficient to induce PNFs unless an injury to the nerve occurs. Malignant transformation of PNFs to MPNSTs requires at least two additional genetic alterations: sequential inactivation of CDKN2A, and then either SUZ12 or EED - two essential components of Polycomb Repressive Complex 2 (PRC2). PRC2 catalyzes histone modification H3K27me3 to repress gene expression throughout the genome. Loss of PRC2 specifically observed in MPNSTs, but not in benign tumors, suggests that PRC2-mediated H3K27me3 normally represses expression of the oncogenic drivers responsible for malignant transformation of PNFs to MPNSTs. However, Eed/PRC2 is dispensable during normal mouse SC development and myelination. Further, loss of the Eed/PRC2 tumor suppressor unexpectedly inhibits proliferation of injury-induced reprogrammed SCs, accompanied by derepression of Cdkn2a expression. Here, we propose to test two related hypotheses: (1) the developmental Nf1-/- Remak pocket defect and its associated axonal degeneration (nerve injury) drive Nf1-/- SCs to form PNFs and (2) nerve injury response induces an epigenomic switch, rendering reprogrammed PNFs or SCs susceptible to malignant transformation by sequential loss of CDKN2A and PRC2. We will determine the role of the developmental Remak pocket defect in NF1-MPNST formation (Aim 1), investigate tumor suppressive mechanisms in injury-induced reprogramed SCs (Aim 2), and develop therapeutic strategies based on the injury-induced epigenomic switch in reprogrammed SCs (Aim 3). We will identify injury-induced and PRC2- repressed oncogenic drivers for MPNST formation via epigenomic approaches, develop synergistic therapies using a high-throughput drug repurposing screen, and test them GEM- and patient-derived preclinical models.


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 = -$6,588 )
2025	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	4	6/17/2025	NON-COMPETING CONTINUATION	$0
2025	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/5/2025	NON-COMPETING CONTINUATION	-$412,097
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	5	5/7/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$405,509
														Subtotal = -$6,588

Issue Date FY: 2024 ( Subtotal = $646,852 )
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	4/10/2024	NON-COMPETING CONTINUATION	$46,681
2024	2024	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/27/2024	NON-COMPETING CONTINUATION	$600,171
														Subtotal = $646,852

Issue Date FY: 2023 ( Subtotal = $677,114 )
2023	2023	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	3/30/2023	NON-COMPETING CONTINUATION	$677,114
														Subtotal = $677,114

Issue Date FY: 2022 ( Subtotal = $703,939 )
2022	2022	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/30/2022	NON-COMPETING CONTINUATION	$703,939
														Subtotal = $703,939

Issue Date FY: 2021 ( Subtotal = $723,312 )
2021	2021	CHILDREN'S RESEARCH INSTITUTE	111 MICHIGAN AVE NW	WASHINGTON	DC	20010	DISTRICT OF COLUMBIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/15/2021	NEW	$723,312
														Subtotal = $723,312

Grand Total All Awards = $2,744,629

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Developmental Origin, Injury and Epigenomic Regulation of NF1-Associated Peripheral Nerve Sheath Tumors

Award Number: R01NS116421

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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