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Genomic Architecture of LGL Leukemia

Award Number: R01CA178393
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Genomic Architecture of LGL Leukemia - PROJECT SUMMARY/ABSTRACT Large granular lymphocytic leukemia (LGLL) results from a clonal expansion of antigen-driven cytotoxic T lymphocytes, or natural killer (NK) cells. LGLL is characterized by an inability to complete activation-induced cell death (AICD), inflammatory cytokine production, autoimmune disease, and cytopenias (primarily neutropenia and anemia). In the absence of molecularly targeted therapeutics, treatments include broad immunosuppressive agents that exhibit slow and incomplete responses. We have identified recurrent somatic variants along with changes in gene expression, chromatin accessibility, histone code, and DNA methylation to define the molecular pathogenesis of LGLL. These efforts revealed molecular diversity among LGLL patients that parallels the dramatic clinical heterogeneity of this disease. Common mutational events included a preponderance of somatic activation mutations in STAT3 followed by mutation of multiple epigenetic modifier genes (TET2, DNMT3A, KMT2D, SETD1B, KDM6A), with frequent co-occurrence of the two. This project will precisely define the consequences of these identified molecular alterations and their impact on LGLL biology and function. In Aim 1, we will use readouts of proliferation, STAT3 activation, cell signaling, cytokine profiling, and gene expression in cell line models and primary patient and healthy donor samples to define and compare the impact of the most frequently detected LGLL mutations. In Aim 2, we will study the consequences of the recurrent STAT3, TET2, and DNMT3A mutations on T- and NK-cell DNA methylation. We will also define the impact of these mutations on susceptibility to an epigenetic targeting agent that reduces DNA methylation. In Aim 3, we will use computational analysis of single-cell multi-omic datasets to define key molecular events downstream of recurrent somatic variants in both T- and NK-LGLL. We will identify differences in clonal structure, gene expression, chromatin accessibility, cell-cell interaction, and active transcription factors and their targets between the malignant cells and their normal counterparts, and between the major mutation groups in LGLL. Finally, we will integrate our gene expression with other reference single-cell datasets of cytotoxic T-cell antiviral responses, tumor infiltration, and cell therapy. Together, these aims will identify and characterize cell-type-specific functional changes in LGLL of high translational relevance, leading to the identification of predictive markers of treatment response and new targets for therapeutic intervention.


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 = $680,771 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	7	9/10/2025	NON-COMPETING CONTINUATION	$680,771
														Subtotal = $680,771

Issue Date FY: 2024 ( Subtotal = $680,771 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	6	8/14/2024	COMPETING CONTINUATION	$680,771
														Subtotal = $680,771

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	9/18/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	1/7/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $608,386 )
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	5	1/17/2020	NON-COMPETING CONTINUATION	$60,839
2020	2020	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	5	12/19/2019	NON-COMPETING CONTINUATION	$547,547
														Subtotal = $608,386

Issue Date FY: 2019 ( Subtotal = $590,474 )
2019	2019	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	4	11/21/2018	NON-COMPETING CONTINUATION	$590,474
														Subtotal = $590,474

Issue Date FY: 2018 ( Subtotal = $609,097 )
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	3	5/23/2018	NON-COMPETING CONTINUATION	$60,910
2018	2018	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	3	11/16/2017	NON-COMPETING CONTINUATION	$548,187
														Subtotal = $609,097

Issue Date FY: 2017 ( Subtotal = $609,457 )
2017	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	2	11/9/2016	NON-COMPETING CONTINUATION	$548,511
2017	2017	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	2	6/7/2017	NON-COMPETING CONTINUATION	$60,946
														Subtotal = $609,457

Issue Date FY: 2016 ( Subtotal = $630,575 )
2016	2016	UNIVERSITY OF VIRGINIA	P.O. BOX 400195	CHARLOTTESVILLE	VA	22904	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	1	11/25/2015	NEW	$630,575
														Subtotal = $630,575

Grand Total All Awards = $4,409,531

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Genomic Architecture of LGL Leukemia

Award Number: R01CA178393

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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