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Investigating Type I Interferon response and differentiation in FLT3-inhibitor persistent acute myeloid leukemia

Award Number: R37CA307677
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Investigating Type I Interferon response and differentiation in FLT3-inhibitor persistent acute myeloid leukemia - PROJECT SUMMARY Acute myeloid leukemia (AML) is a genetically and cellularly heterogenous disease characterized by the expansion of hematopoietic cells across a range of cell states from stem-like cells to differentiated myeloid cells. The most mutated genes in AML are DNMT3A, NPM1 and the receptor tyrosine kinase FLT3. Despite early clinical responses, most patients relapse, and FLT3-mutant clones are not always eradicated. Our lab has developed genetically engineered mouse models of acute myeloid leukemia that are capable of activating mutations in Flt3 with Dre-recombinase, and then genetically reverting them with Cre-recombinase. We have used these models to benchmark Flt3 oncogene-addiction against best-in-class small molecule kinase inhibitors of FLT3, observing difference in disease remission and relapse. These studies have refined our interest on identifying which cells along the hematopoietic hierarchy are capable of driving relapse and which molecular pathways underlie their survival following chemical/genetic inhibition of FLT3. The major goal of this proposal is to understand the cellular mechanisms that maintain FLT3-mutant clone persistence during targeted therapy. Our preliminary data indicate that Flt3-inhibtion results in a profound differentiation response and induction of Type I Interferon signaling. We will complete integrative studies with human specimen and our innovative multi- recombinase mouse models of leukemia to derive clinically meaningful insights from mechanistic observations in model systems. In aim 1 we will determine which cells are capable of propagating leukemic disease and resolve cellular reservoirs of leukemic stem cell activity. We will perform these studies using genetically engineered mouse models, serial transplantation of purified cell populations, and functional cell ablation studies. We hypothesize that FLT3-inhibtion induced differentiation generates mature cells that are capable of reacquiring stem-like properties and drive relapse. These studies will resolve which cells are necessary to eliminate to prevent leukemic recurrence and provide a focusing lens for improving targeted therapy and relapse detection. In aim 2 we will determine the role of Type I Interferon signaling in differentiation and relapse using gain/loss of function systems. We will evaluate the therapeutic potential of interferon treatment in conjunction with FLT3 kinase inhibition. Finally, we will assess the clonal diversity of leukemic cell states using lentiviral barcoding and single cell RNA sequencing to evaluate which cells can induce an Interferon response, and what their long-term fate is following treatment. We hypothesize that Interferon signaling is necessary to potentiate FLT3-inhibitor driven differentiation, and that combined treatment will extend survival. We anticipate that these studies will more broadly inform the intersection between inflammation and differentiation in AML therapy.


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 = $434,969 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Treatment Research	000	1	4/29/2026	NEW	$434,969
														Subtotal = $434,969

Grand Total All Awards = $434,969

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Investigating Type I Interferon response and differentiation in FLT3-inhibitor persistent acute myeloid leukemia

Award Number: R37CA307677

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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