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Characterization of short H2A Oncohistones in Cancer

Award Number: K08CA256167
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Characterization of short H2A Oncohistones in Cancer - Abstract An emerging body of literature has shown that nucleosomes, the fundamental subunit of chromatin, are destabilized in a broad array of common cancers. This destabilization was previously thought to require cancer-specific mutations in histone-encoding genes, called “oncohistones”. We identified a new mechanism by which cancers can acquire unstable nucleosomes, through upregulation of the nucleosome-poisoning histone H2A variant H2A.B. This variant is normally expressed in testis only, where it contributes to the unique chromatin environment in sperm. We compared the amino acid sequences of H2A.B and H2A and identified oncohistone features in the wildtype H2A.B sequence, suggesting that this is a readymade oncohistone sitting in our genomes. Consistent with this hypothesis, we identified H2A.B expression in 50% of diffuse large B-cell lymphomas and 5-10% of many other common malignancies but not in normal tissue outside of testis. We also found unique patterns of alternative splicing in H2A.B-expressing cancers, and these changes were previously reported in the context of nucleosome destabilization. Finally, we performed knockdown studies and found that H2A.B reduction impairs cancer cell growth in several different lymphoma cell lines, results that are supported by large-scale CRISPR studies. Together, these data substantially expand the number of cancers that may be driven by oncohistone biology. However, the contribution of H2A.B to oncogenesis is not known. This proposal will identify the effects of H2A.B on the transcriptome and epigenome in order to find new vulnerabilities in H2A.B-positive cancers. In aim 1, we employ RNA sequencing to identify changes in gene expression and alternative splicing in response to induction or reduction of H2A.B. In aim 2 we use chromatin profiling methods developed in the Henikoff lab to study the impact of H2A.B expression on the epigenome. In aim 3 we use data from aims 1 and 2 to identify vulnerabilities in H2A.B-positive cancers including investigation of aclarubicin, an anthracycline with similar efficacy but much more favorable side effect profile than doxorubicin. The experiments in this proposal will elucidate the role of H2A.B in cancer and identify novel therapeutic vulnerabilities.


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 = $211,694 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Research Manpower	000	4	7/31/2025	NON-COMPETING CONTINUATION	$211,694
														Subtotal = $211,694

Issue Date FY: 2024 ( Subtotal = $211,694 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Research Manpower	000	3	7/19/2024	NON-COMPETING CONTINUATION	$211,694
														Subtotal = $211,694

Issue Date FY: 2023 ( Subtotal = $211,694 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Research Manpower	000	2	8/8/2023	NON-COMPETING CONTINUATION	$211,694
														Subtotal = $211,694

Issue Date FY: 2022 ( Subtotal = $211,694 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Cancer Research Manpower	000	1	8/22/2022	NEW	$211,694
														Subtotal = $211,694

Grand Total All Awards = $846,776

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Characterization of short H2A Oncohistones in Cancer

Award Number: K08CA256167

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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