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Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments

Award Number: R37CA271172
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/30/2022
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments - PROJECT SUMMARY/ABSTRACT Myeloproliferative neoplasm (MPN) is a hematologic malignancy characterized by the clonal outgrowth of hematopoietic cells with a somatically acquired mutation most commonly in JAK2 (JAK2V617F), which leads to excessive production of myeloid lineage cells. Patients with early stage MPN can spontaneously progress to myelofibrosis, a more aggressive stage of the disease with an average survival rate of two years. Moreover, MPN patients have a significant risk of developing acute myeloid leukemia (AML). The traditional approach to therapy in MPN is simply to reduce the risk of blood clots with aspirin, manage symptoms, and observe for progression of the disease. Therapeutic intervention is focused on patients with late stage disease, mostly due to the lack of currently available therapies that halt progression. There is thus a need for interventions that impact disease progression in MPN. Preliminary work by the laboratory of Dr. Fleischman, in collaboration with mathematical modelers Komarova and Wodarz, has shown that inflammation can accelerate the growth rate of JAK2V617F mutant cells relative to JAK2WT cells, and that this can potentially have a variety of consequences for the evolution of mutant cells at homeostasis. This suggests the possibility of a new treatment modality for early stage MPN, in which the evolutionary fate of the JAK2V617F mutants is altered and disease progression is delayed or halted. The overall goal of this proposal is to investigate how this can be achieved. In Aim 1, experiments are proposed that document the dynamics of JAK2WT and JAK2V617F mutant cells in isolation with and without inflammation for the purposes of model construction and parameterization. We will also interrogate the intracellular mechanisms responsible for the differential response of JAK2V617F mutants to inflammation. In Aim 2 we will perform experiments in which JAK2WT and JAK2V617F mutant cells are combined in mouse models with and without inflammation. This will quantify how the number of mutants influence the kinetic parameters of wild- type cells, which is important because we know that mutants themselves can increase inflammation and hence alter the dynamics. In Aim 3 we will measure how a panel of existing drugs impact the kinetic parameters of cells and use our model to predict combinations and dosing schedules that will lead to diminution of the mutant cells. Many treatment scenarios (in sequence and in combination) will be explored, and the most promising therapeutic approaches predicted by the model will be tested experimentally. This can identify better and currently unknown ways in which to utilize existing drugs. On a more exploratory level, the validated mathematical model can suggest which parameter(s) to target in which ways to make treatment more efficient than can be currently done. This information would facilitate development of future treatments and guide drug discovery and could be translated into a future clinical trial.


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 = $539,793 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	4	3/20/2025	NON-COMPETING CONTINUATION	$485,814
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	003	4	5/22/2025	NON-COMPETING CONTINUATION	$53,979
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	4	4/25/2025	NON-COMPETING CONTINUATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	002	3	4/28/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $539,793

Issue Date FY: 2024 ( Subtotal = $600,119 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	3	4/23/2024	SUPPLEMENT FOR EXPANSION	$87,317
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	3	4/15/2024	NON-COMPETING CONTINUATION	$512,802
														Subtotal = $600,119

Issue Date FY: 2023 ( Subtotal = $533,981 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	2	4/3/2023	NON-COMPETING CONTINUATION	$533,981
														Subtotal = $533,981

Issue Date FY: 2022 ( Subtotal = $544,880 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	1	5/30/2022	NEW	$544,880
														Subtotal = $544,880

Grand Total All Awards = $2,218,773

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Effect of inflammation on JAK2 mutant evolution in the hematopoietic system: mathematical models and experiments

Award Number: R37CA271172

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/30/2022

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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