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Hepatitis B virus integrations in KMT2B drive hepatocellular carcinoma

Award Number: R01CA272578
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Hepatitis B virus integrations in KMT2B drive hepatocellular carcinoma - ABSTRACT Chronic infection by hepatitis B virus (HBV) is the leading cause of hepatocellular carcinoma (HCC). HBV alone is responsible for more than 3% of worldwide cancer deaths of all cancer sites combined. How HBV promotes carcinogenesis is not fully understood, leading to limited therapeutic options for advanced diseases. We previously revealed that 10% of HBV-associated HCC tumors carry clonal integrations of HBV in the KMT2B gene locus in cancer cell genomes. All these integrations are located between exons 3 and 6 of the KMT2B gene. KMT2B is the only close homolog of KMT2A (also known as MLL1). It has been well established that the chromosomal translocations affecting KMT2A are the primary drivers of infant mixed lineage leukemia. HBV integrations in KMT2B in HCC may mirror KMT2A rearrangements in leukemia, but its function has not been studied. We have identified patient-derived HCC cell lines carrying HBV integrations in KMT2B. Using these cell lines and RNA-seq data of HCC tumors with HBV integrations in KMT2B, we found that these integrations lead to expression of truncated KMT2B from the N-terminus to 697 to 906 amino acid residues. Knockout of the KMT2B truncation in an integration-carrying cell line suppressed cell proliferation in vitro. Overexpression of a KMT2B truncation transformed normal human hepatocytes in vitro and induced tumor growth in vivo in hydrodynamic injection-based mouse models. Mechanistically, we found the KMT2B truncation sequestered the tumor suppressor MENIN from the KMT2A/B histone methyltransferase complex and chromosome. A KMT2B truncation carrying a mutation that blocks MENIN binding failed to promote tumor formation in vivo. Based on these preliminary data, our central hypothesis is that HBV integrations in KMT2B produce truncations, which sequester MENIN from KMT2B complex and promote hepatocellular carcinoma. To test this hypothesis, we will determine the oncogenic function of KMT2B truncations, using various in vitro and in vivo models (Aim 1), and determine the mechanism of KMT2B truncation-triggered tumorigenesis (Aim2). Specifically, a new genetic engineered mouse model of HCC will be generated and a potential targeted agent for HCC with HBV integrations in KMT2B will be tested. The proposed studies aim to establish the oncogenic driving function and mechanism of HBV integrations in KMT2B in HCC, which cause 35,000 HCC cases every year. It is among the most common cancer-causing genetic alterations but it is significantly understudied. The completion of the proposed studies will discover a novel oncovirus-driving, epigenetic mechanism of HCC development and provide information for developing prevention approaches, early detection assays, and targeted therapeutics for affected individuals.


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: 2024 ( Subtotal = $404,870 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	002	3	7/24/2024	NON-COMPETING CONTINUATION	$404,870
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	2	3/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$78,043
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Biology Research	000	1	3/26/2024	NEW	-$78,043
														Subtotal = $404,870

Issue Date FY: 2023 ( Subtotal = $462,623 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	2	7/25/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$462,623
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	7/25/2023	NEW	$0
														Subtotal = $462,623

Issue Date FY: 2022 ( Subtotal = $453,403 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	7/7/2022	NEW	$453,403
														Subtotal = $453,403

Grand Total All Awards = $1,320,896

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Hepatitis B virus integrations in KMT2B drive hepatocellular carcinoma

Award Number: R01CA272578

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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