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Regulation of Protein Synthesis in Leukemia Stem Cells

Award Number: R37CA273232
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/21/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Regulation of Protein Synthesis in Leukemia Stem Cells - Summary/Abstract Leukemia stem cells (LSCs) promote therapeutic resistance and poor clinical outcomes in acute myeloid leukemia (AML). Central to the function of LSCs is a capacity for aberrant self-renewal, but the mechanisms underlying this activity are not well understood. The long-term goal is to identify these mechanisms to develop new therapies that can eradicate LSCs to improve clinical outcomes. The overall objectives in this application are to (i) determine if LSCs from specific genetic subtypes of AML are dependent on regulation of protein synthesis, (ii) determine whether LSCs in high-risk hematopoietic stem cell (HSC)-like AMLs are more dependent on regulated protein synthesis, and (iii) test a novel therapeutic strategy inhibiting protein synthesis in LSCs. The central hypothesis is that LSCs aberrantly self-renew by adopting from normal HSCs a dependence on tightly regulated protein synthesis. The rationale for this project is based on the finding that the cell surface marker CD99 is selectively overexpressed on LSCs and serves to regulate protein synthesis to promote LSC function. This offers a strong scientific framework by which new strategies to deplete LSCs can be developed. The central hypothesis will be tested by pursuing three specific aims: 1) Determining the role of regulated protein synthesis in promoting LSC function; 2) Determining if the cell-of-origin of AML influences the dependence of LSCs on regulated protein synthesis; and 3) Determining if inhibition of protein synthesis can deplete LSCs in high-risk AML. In the first aim, genetically engineered mice will be used to generate models of AML lacking CD99, to test if this leads to dysregulated protein synthesis that impairs LSC self-renewal. LSCs from these models will be evaluated to determine if they require low protein synthesis rates to prevent induction of tumor suppressors, the unfolded protein response, and the integrated stress response. Ribosome profiling will be performed to identify key LSC regulators selectively translated in the context of regulated protein synthesis. In the second aim, we will generate a mouse model of HSC-like AML which mimics high-risk human AML. We will assess if LSCs in HSC- like AML exhibit heightened sensitivity to dysregulated protein synthesis. These studies will be complemented with an evaluation of protein synthesis in HSC-like human LSCs to determine if they also require maintenance of low levels of protein synthesis. The third aim will test if the combination of a ribosome biogenesis-inhibitor with a BCL2-inhibitor currently used to treat AML can eradicate LSCs in high-risk HSC-like AML. The proposal is innovative, in the applicant’s opinion, because it aims to leverage a novel LSC-specific cell surface marker to establish a new paradigm for understanding mechanisms underlying LSC self-renewal. The proposed research is significant because it is expected to provide a strong scientific justification for the development of therapies inhibiting protein synthesis to overcome therapeutic resistance in patients with high-risk AML. Ultimately, the knowledge gained from these studies may offer insights into the mechanisms that promote the function of cancer stem cells in general, opening up opportunities for the development of new strategies to treat cancer.


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 = $475,420 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	3	9/4/2025	NON-COMPETING CONTINUATION	$475,420
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	2	8/14/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $475,420

Issue Date FY: 2024 ( Subtotal = $518,885 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	003	2	8/15/2024	SUPPLEMENT FOR EXPANSION	$67,237
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	002	2	8/9/2024	NON-COMPETING CONTINUATION	$451,648
2024	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	1	10/13/2023	NEW	$0
2024	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	001	1	1/23/2024	NEW	$0
														Subtotal = $518,885

Issue Date FY: 2023 ( Subtotal = $475,420 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cancer Biology Research	000	1	9/21/2023	NEW	$475,420
														Subtotal = $475,420

Grand Total All Awards = $1,469,725

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Regulation of Protein Synthesis in Leukemia Stem Cells

Award Number: R37CA273232

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/21/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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