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Role of HOTTIP/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells

Award Number: R01CA264932
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Role of HOTTIP/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells - Abstract: Self-renewal is an indispensable property that allows stem cells to regenerate and maintain the homeostasis of functionally diverse cell populations. Dergulation of self-renewal in hematopoietic stem cell (HSC) directly links to a number of hematopoietic degenerative disorders including bone marrow failure and various blood diseases, whereas its aberrant activation is a defining and indispensable feature of leukemia stem cells (LSCs) that sustain the malignant phenotypes. We and others have shown that self-renewal of acute myeloid leukemia (AML) stem cells heavily rely on the key component of canonical Wnt signaling pathway, â-catenin and the homeobox protein, HOXA9 that are largely dispensable for adult HSCs. Although these findings reveal a contrasting functional requirement and a potential therapeutic opportunity for AML, development of small molecule inhibitors against oncogenic transcription factors has so far met with very little success largely due to our lack of understanding about the molecular regulations of these proteins in mediating hematopoietic self-renewal, which has significantly hindered progress in developing effective therapeutic strategies to treat the resultant diseases. Intriguingly, we have recently revealed coregulation of both canonical Wnt pathway and posterior HOXA loci including HOXA9 by the long non-coding RNA (lncRNA), HOTTIP. Strikingly, we also report a novel crosstalk between â-catenin and HOXA9 that can override their individual requirement in both mouse and human AML of HSC origins. In search for crucial mediators for â-catenin and Hoxa9 functions, we further identified that protein arginine methyltransferase 1 (PRMT1), which also implicates in DNA damage and repair (DDR), can functionally replace HOXA9 or â-catenin in AML stem cell originated from HSCs. PRMT1 together with DDR complex are unbiasedly isolated along with CTCF/cohesin complex, hematopoietic transcription factors (TFs) and nucleosome remodeling factors as HOTTIP interacting partners by ChIRP-MS in AML cells. These findings not only discover a novel HOTTIP/â-catenin-HOXA9/PRMT1 axis critical for mediating hematopoietic self-renewal, but also lead to central hypothesis that HOTTIP/â-catenin-HOXA9/PRMT1 axis coordinates hematopoietic self-renewal and characterization of the functions of individual components and their crosstalk along the axis regulates hematopoietic specific transcription networks and DDR pathways to modulate hematopoietic self-renewal in the disease setting. In this proposal, we will 1 decipher cooperative action of HOTTIP and hematopoietic TFs in regulating HOXA9 and â-catenin axis; 2) dissect the molecular functions and regulation of â-cateninHOXA9/Prmt1 axis during normal and malignant hematopoiesis. Success completion of proposed studies not only will establish the molecular principles but also facilitate the design of specific therapeutics in modulating self-renewal activities in normal and malignant stem cells, which can be potentially translated into patient benefits. The proposed project has resulted in a long-time collaboration between Dr. Huang from Penn State Hershey Medical Center and Dr. So from KCL who generated preliminary data together. Dr. So who provides proposed project with unique expertise, animal models and patient samples will be extremely complementary and significantly synergize with my endeavour to characterize the upstream HOTTIP/â-catenin-Hoxa9 functions and their regulations to depict a comprehensive picture for the roles of HOTTIP/â-catenin-Hoxa9/Prmt1 axis in normal HSCs and AML leukemia stem cells (LSCs).


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: 2026 ( Subtotal = $506,196 )
2026	2026	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	5	8/3/2026	NON-COMPETING CONTINUATION	$303,207
2026	2026	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	001	5	8/12/2026	SUPPLEMENT FOR EXPANSION	$202,989
														Subtotal = $506,196

Issue Date FY: 2025 ( Subtotal = $505,747 )
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	001	4	9/10/2025	SUPPLEMENT FOR EXPANSION	$202,540
2025	2025	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	4	9/8/2025	NON-COMPETING CONTINUATION	$303,207
														Subtotal = $505,747

Issue Date FY: 2024 ( Subtotal = $479,644 )
2024	2024	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	3	6/25/2024	NON-COMPETING CONTINUATION	$479,644
														Subtotal = $479,644

Issue Date FY: 2023 ( Subtotal = $495,056 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY	500 UNIVERSITY DRIVE	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	2	6/22/2023	NON-COMPETING CONTINUATION	$495,056
														Subtotal = $495,056

Issue Date FY: 2022 ( Subtotal = $520,285 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	500 UNIVERSITY AVE RM C1607	HERSHEY	PA	17033	DAUPHIN	USA	Cancer Biology Research	000	1	7/1/2022	NEW	$520,285
														Subtotal = $520,285

Grand Total All Awards = $2,506,928

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Role of HOTTIP/beta-catenin-HOXA9/PRMT1 axis in hematopoietic and leukemic stem cells

Award Number: R01CA264932

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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