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Elucidating the Functional and Mechanistic Roles of LINE-1 Retrotransposons in Myeloid Leukemia

Award Number: R01CA259581
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Elucidating the Functional and Mechanistic Roles of LINE-1 Retrotransposons in Myeloid Leukemia - PROJECT SUMMARY The role of retrotransposons in human cancer has been historically underappreciated both because they have been dismissed as unimportant ‘junk’ DNA, and because their high repetition and variation pose significant technical challenges. There are ~500,000 copies of LINE-1 (or L1) retrotransposons occupying 17% of the human genome, but only ~100 full-length human-specific L1 elements (L1Hs) are capable of active retrotransposition. L1-encoded proteins also mobilize non-autonomous retrotransposons, noncoding RNAs and mRNAs, leading to the generation of a third of human DNA. As such, L1s have been considered mostly deleterious because their activity can lead to genetic mutations and chromosomal alterations that contribute to human disorders including cancer. By domain-based CRISPR screens of human chromatin regulators, we identified MPP8, a component of the HUSH complex responsible for the silencing of L1 retrotransposons, as a selective epigenetic dependency of acute myeloid leukemia (AML) cells. While dispensable for normal hematopoiesis, MPP8 loss impaired AML initiation and maintenance by reactivating L1s. Ectopic L1 activation phenocopied MPP8 loss, whereas blocking L1 retrotransposition abrogated the phenotypes. L1 suppression is associated with therapy resistance and poor prognosis in human AML patients. Hence, while retrotransposons are historically recognized for their cancer-promoting roles as sources of genetic instability and somatic mutations, our findings support an unexpected ‘tumor-suppressive’ function for retrotransposons as a selective dependency for myeloid leukemia. The goal of this project is to elucidate the functional and mechanistic roles of L1 retrotransposons as a new regulatory pathway in AML pathophysiology. The central hypotheses are that L1 retrotransposons function to modulate DNA damage response and/or inflammatory signaling in AML-initiating cells, and that L1 activity controls therapeutic response to DNA damage-inducing agents in myeloid leukemia. Our hypotheses have been formulated on the basis of extensive preliminary studies using orthogonal approaches to modulate L1 function in physiologically relevant AML models and a newly discovered molecular link between suppression of retrotransposons and propagation of cancer-initiating cells. Guided by these findings, these hypotheses will be tested by three specific aims: 1) Establish the functional roles of L1 retrotransposons in the clonal evolution of myeloid leukemia. 2) Elucidate the mechanistic roles of L1 retrotransposons in AML pathogenesis. 3) Determine the effects of modulating retrotransposon activity on therapeutic response to DNA damage-inducing agents in myeloid leukemia. Taken together, these studies will not only elucidate the mechanistic basis for the unexpected ‘tumor-suppressive’ function for retrotransposon activity in myeloid leukemia, but also establish a new paradigm for mobile DNA elements as a previously uncharted regulatory pathway in leukemia biology, whose intervention may lead to improved anti-leukemia therapies.


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 = $482,075 )
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	5	11/15/2024	NON-COMPETING CONTINUATION	$433,868
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	5	11/22/2024	NON-COMPETING CONTINUATION	$0
2025	2025	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	005	5	6/4/2025	NON-COMPETING CONTINUATION	$48,207
2025	2023	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	004	3	1/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$48,897
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	003	2	1/17/2025	NON-COMPETING CONTINUATION	-$1
2025	2022	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	002	1	1/17/2025	NEW	-$48,896
														Subtotal = $482,075

Issue Date FY: 2024 ( Subtotal = $463,269 )
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$24,382
2024	2024	ST JUDE CHILDREN'S RESEARCH HOSPITAL INC	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	000	4	12/18/2023	NON-COMPETING CONTINUATION	$438,887
														Subtotal = $463,269

Issue Date FY: 2023 ( Subtotal = $479,804 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	002	2	9/8/2023	NON-COMPETING CONTINUATION	-$417,123
2023	2023	ST. JUDE CHILDREN'S RESEARCH HOSPITAL, INC.	262 DANNY THOMAS PL	MEMPHIS	TN	38105	SHELBY	USA	Cancer Biology Research	003	3	9/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$479,803
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	2	11/15/2022	NON-COMPETING CONTINUATION	$383,073
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	2	3/15/2023	NON-COMPETING CONTINUATION	$34,051
														Subtotal = $479,804

Issue Date FY: 2022 ( Subtotal = $435,519 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	1	11/30/2021	NEW	$435,519
														Subtotal = $435,519

Grand Total All Awards = $1,860,667

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Elucidating the Functional and Mechanistic Roles of LINE-1 Retrotransposons in Myeloid Leukemia

Award Number: R01CA259581

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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