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Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis

Award Number: F31CA265285
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis - Abstract: Diffuse intrinsic pontine glioma (DIPG) is an incurable high-grade glioma arising in the brainstem primarily in younger children. DIPG 2-year survival rate is <10% due to its unresectable tumor location and resistance to radiation and available therapeutics. This emphasizes the need for better understanding of the underlying pathogenesis of DIPG to identify new therapeutic vulnerabilities. Histone H3 Lys27Met (K27M) mutations are a unifying molecular feature observed ~80% of DIPGs and pediatric diffuse midline gliomas (DMG). The high frequency of K27M and their exclusivity to childhood DIPG and DMG suggests K27M has a unique selective advantage in a distinct spatiotemporal setting for tumorigenesis. Understanding the regional selectively of K27M and its phenotypic and molecular effects will further elucidate oncogenic mechanisms and help identify new and better treatment options. The Baker laboratory developed a genetically engineered mouse model harboring a conditional knock-in of K27M into the endogenous H3f3a locus which allows the mutation to be studied in a physiologically and developmentally relevant manner. With this model, we showed K27M cooperates with Pdgfra activation and or p53 loss to drive spontaneous gliomagenesis selectively in brainstem and hindbrain locations. K27M causes dramatic loss of the repressive H3K27me3 but only specific changes in gene expression related to neurodevelopment. Single-cell RNA-seq of human K27M DIPGs reveals oligodendrocyte precursors (OPC) are the main proliferative and stem-like population present in DIPGs. We have also showed that depletion of K27M in patient-derived xenografts induces oligodendrocyte (OL) differentiation signatures, decreases stemness signatures, and reduces proliferation and tumor growth. In total, these studies indicate a role for K27M in regional selectivity of brainstem tumorigenesis along with altered OL differentiation, promoting OPC-like state. However, many questions still remain regarding K27M and DIPG. Why is K27M found almost exclusively in brainstem and midline pediatric glioma? What are the oncogenic effects and mechanisms of K27M alone? I will utilize our K27M knock-in mice to dissect the regional effects of H3 K27M on glial development and tumorigenesis in vivo (Aim 1) and evaluate the regional K27M-mediated epigenetic and transcriptomic dysregulation in oligodendrocyte development to identify K27M DIPG dependencies (Aim 2). Through completion of these studies, we will gain insights into the molecular mechanisms and spatiotemporal context of K27M that disrupt development and promote tumorigenesis which will help to direct therapeutic development to target the molecular programs involved that are specific to region and cellular state.


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 = -$1,182 )
2025	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL # 1500	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	3	4/24/2025	NON-COMPETING CONTINUATION	-$1,182
														Subtotal = -$1,182

Issue Date FY: 2023 ( Subtotal = $43,694 )
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	3	6/19/2023	NON-COMPETING CONTINUATION	$43,694
														Subtotal = $43,694

Issue Date FY: 2022 ( Subtotal = $42,752 )
2022	2022	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	2	5/24/2022	NON-COMPETING CONTINUATION	$42,752
														Subtotal = $42,752

Issue Date FY: 2021 ( Subtotal = $42,036 )
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	003	1	8/26/2021	NEW	$0
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	002	1	8/26/2021	NEW	$42,036
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	001	1	8/23/2021	NEW	-$42,036
2021	2021	ST. JUDE CHILDREN'S RESEARCH HOSPITAL GRADUATE SCHOOL OF BIOMEDICAL SCIENCES, LLC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Research Manpower	000	1	7/26/2021	NEW	$42,036
														Subtotal = $42,036

Grand Total All Awards = $127,300

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Regional selectivity of oncohistone H3K27M on glial development and glioma pathogenesis

Award Number: F31CA265285

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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