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Role of IL-10R signaling in inflammation induced exhaustion of HSC and emergence of JAK2V617F clonal hematopoiesis

Award Number: R01DK136069
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Revised Project Summary Age and chronic inflammatory stress drive the emergence of mutant bone marrow stem cells that can lead to specific hematologic malignancy associated mutations allow HSC to resist specific stressors could be leveraged toward therapies aimed at neutralizing the selective advantage of the malignant clone. We have recently found that patients with myeloproliferative neoplasm (MPN) have a dampened response to the anti-inflammatory cytokine IL-10 and this leads to persistent production of the inflammatory cytokine TNFα. In a murine Jak2V617F MPN model, pharmacologic blockade of IL-10R signaling enhances the selective advantage of Jak2V617F mutant cells. The objective of this project is to define how JAK2V617F mutant HSC gain a selective advantage over wild-type (WT) HSC when IL-10R is blocked. Our central hypothesis is that dampened IL-10R signaling creates an inflammatory state that negatively affects WT but not JAK2V617F mutant HSC, thus endowing JAK2V617F mutant cells a selective advantage. Moreover, we hypothesize that dampened IL-10R signaling is an intrinsic feature of those predisposed to acquire MPN. In Aim 1 we will determine the prevalence of an IL-10 resistance phenotype among MPN families. We have found that MPN patients display an inability to respond to IL-10, which we term the “IL-10 resistance phenotype”. However, cases with a family history of MPN have not been systematically evaluated for the phenotype, nor have unaffected family members. We will determine the prevalence of the IL-10 resistance phenotype in affected and unaffected members of our growing MPN family registry which currently contains 53 MPN families. In Aim 2 we will identify the genetic basis for blunted IL-10R signaling in MPN. We will perform targeted DNA sequencing and gene expression profiling (i.e., RNA-seq, ChIP-seq, and differential DNA methylation analysis) to identify the underlying mechanism responsible for dampened IL-10 signaling in MPN. Using sorted peripheral blood monocytes we will use Illumina Infinium MethylationEPIC chips to determine if MPN patients and unaffected family members with blunted IL-10 signaling have differential methylation of IL-10R signaling genes. Gene expression profiling will be performed in parallel to determine if the methylation pattern accurately predicts gene expression. We will also perform targeted DNA sequencing, focusing on cytokine receptor pathway genes, and paying close attention to any genes found to have differential methylation and/or expression, to identify the genetic basis for blunted IL-10 signaling in MPN patients.


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: 2024 ( Subtotal = $324,706 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/16/2024	NON-COMPETING CONTINUATION	$214,642
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	3	8/20/2024	SUPPLEMENT FOR EXPANSION	$90,793
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	5/15/2024	SUPPLEMENT FOR EXPANSION	$19,271
														Subtotal = $324,706

Issue Date FY: 2023 ( Subtotal = $224,260 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	8/1/2023	NON-COMPETING CONTINUATION	$224,260
														Subtotal = $224,260

Issue Date FY: 2022 ( Subtotal = $224,896 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/20/2022	NEW	$224,896
														Subtotal = $224,896

Grand Total All Awards = $773,862

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Role of IL-10R signaling in inflammation induced exhaustion of HSC and emergence of JAK2V617F clonal hematopoiesis

Award Number: R01DK136069

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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