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Dissecting innate immune signaling in pre-leukemia evolution

Award Number: R01CA271455
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/04/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Dissecting innate immune signaling in pre-leukemia evolution - Abstract Clonal hematopoiesis (CH) is an aging associated condition characterized by the clonal outgrowth of mutated pre-leukemic cells. Although individuals with CH are healthy, they are at an increased risk of developing hematopoietic malignancies. To identify cooperating molecular alterations required for malignant transformation of clonal pre-leukemic HSPC, we performed an in vivo shRNA screen and found that shRNAs targeting Traf6 were overwhelmingly enriched in following transformation to overt myeloid leukemias. TRAF6 is an ubiquitin E3 ligase that synthesizes Lysine (K) 63-linked ubiquitin chains on substrates leading to Toll-like receptor (TLR) superfamily pathway activation. In support of our in vivo shRNA screen, promoter hypermethylation and reduced expression of TRAF6 is observed in subsets of myeloid malignancy patients, including ~40-50% of acute myeloid leukemia (AML). Moreover, our preliminary data shows that deletion of Traf6 in pre-leukemic Tet2-deficient HSPC results in an aggressive myeloid neoplasm in part through a novel MYC-dependent mechanism. Based on our findings, we hypothesize that loss of TRAF6 drives subsets of genetically-defined myeloid malignancies, specifically via a novel post-translational modification of MYC resulting in its activation. The objectives of the proposal are to uncover the molecular and cellular basis of TRAF6 deletion on pre-leukemic HSPC function with the long-term goal of uncovering improved therapeutic approaches by investigating the consequences of TRAF6 deletion in models of CH and on leukemia development (Aim 1), identifying the molecular basis of the tumor suppressor-like function of TRAF6 in AML (Aim 2), and evaluating the oncogenic potential of a novel TRAF6-dependent MYC post-translational modification (Aim 3). These studies are highly significant as they will provide critical insight into the progression of pre-leukemic states to overt leukemia as a result of subverting select innate immune pathways, describe a novel disease-modifying role of TLR-TRAF6, and reveal an unreported mechanism of MYC regulation. These studies have direct translational implications and fill an unmet clinical need for genetically- and phenotypically-defined subtypes of AML/MPN.


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 = $638,243 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	001	4	5/23/2025	NON-COMPETING CONTINUATION	$63,825
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	4	3/5/2025	NON-COMPETING CONTINUATION	$574,418
														Subtotal = $638,243

Issue Date FY: 2024 ( Subtotal = $606,333 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	3	2/23/2024	NON-COMPETING CONTINUATION	$574,418
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	001	3	4/17/2024	NON-COMPETING CONTINUATION	$31,915
														Subtotal = $606,333

Issue Date FY: 2023 ( Subtotal = $625,479 )
2023	2023	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	2	3/31/2023	NON-COMPETING CONTINUATION	$625,479
														Subtotal = $625,479

Issue Date FY: 2022 ( Subtotal = $652,991 )
2022	2022	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Cancer Biology Research	000	1	3/4/2022	NEW	$652,991
														Subtotal = $652,991

Grand Total All Awards = $2,523,046

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Dissecting innate immune signaling in pre-leukemia evolution

Award Number: R01CA271455

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/04/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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