Monday, August 18, 2025 8/18/2025

Therapeutic targeting of IRAK4 in MDS

Award Number: R01CA275007
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2027

Group Awards By:

View Award Description

Therapeutic targeting of IRAK4 in MDS - PROJECT SUMMARY/ABSTRACT Spliceosome mutations and alterations in RNA splicing are common in myelodysplastic syndrome (MDS), yet the specific oncogenic changes due to these alterations have not been fully identified. We demonstrated that overexpression of an active isoform of the serine/threonine kinase, IRAK4, is seen in MDS. The active long IRAK4 isoform (IRAK4-L) consists of an N-terminal death domain (DD) and C-terminal kinase domain (KD), which stochastically assembles with the Myddosome complex and results in maximal activation of innate immune signaling pathways. Inclusion of exon 4 in the long isoform is mediated by mutant splicing factor (SF), U2AF1, which results in oncogenic signaling and poor prognosis in MDS/AML (Smith et al., Nature Cell Biology, 2019). Importantly, inhibition of IRAK4-L abrogates leukemic growth in vitro and in vivo. These findings established that mutations in U2AF1 induce expression of therapeutically targetable active IRAK4 isoforms and provide a genetic link to activation of chronic innate immune signaling in MDS. Our preliminary RNA-sequencing studies in primary MDS samples reveal that (i) splicing factor SF3B1 mutations also lead to the active IRAK4-L isoforms via retention of exon 6, and that (ii) a sizable proportion of splicing factor (SF) wild-type MDS patients also exhibit expression of IRAK4-L. We hypothesize that oncogenic IRAK4-L isoforms are critical for the function of SF-mutant (i.e. U2AF1 and SF3B1) and a subset of SF-wildtype MDS disease propagating cells. As such, this proposal will comprehensively evaluate the mechanistic basis of IRAK4-L regulation in SF3B1 and SF-wild type MDS (Aim 1) by using isogenic cell lines expressing the SF3B1 K700E mutants and by altering the expression of splicing modulator PRMT5. Aim 2 will determine downstream regulators of oncogenic IRAK4 isoform activation in MDS. In addition to examination of NF-κB/MAPK signaling, we will perform an unbiased phospho-proteomic screen to identify direct substrates of IRAK4-L and examine their roles in hematopoietic dysfunction. Aim 3 will determine the efficacy of IRAK4-L inhibition in MDS by a clinical-grade IRAK4 kinase inhibitor. In vitro sensitivity and differentiation assays in U2AF1- and SF3B1-mutant, and SF wildtype MDS cells will be conducted. Patient derived xenografts with U2AF1/SF3B1-mutant, and SF wildtype MDS will be treated with the IRAK4 inhibitors to examine for suppression of the disease-propagating cells. We will also determine whether overexpression of IRAK4-long isoforms is predictive of response in an ongoing clinical trial of IRAK4 inhibitor. Taken together, these studies will determine the role of splicing mutation induced IRAK4-L isoform in MDS pathobiology. Importantly, these studies will lead to potential targeted clinical trials with clinically relevant inhibitors of IRAK4 in MDS.


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 = $528,024 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	000	4	7/31/2025	NON-COMPETING CONTINUATION	$528,024
														Subtotal = $528,024

Issue Date FY: 2024 ( Subtotal = $501,623 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	001	3	8/14/2024	NON-COMPETING CONTINUATION	$501,623
2024	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	000	2	12/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $501,623

Issue Date FY: 2023 ( Subtotal = $517,464 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	000	2	8/25/2023	NON-COMPETING CONTINUATION	$517,464
														Subtotal = $517,464

Issue Date FY: 2022 ( Subtotal = $545,024 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	001	1	9/13/2022	NEW	$95,537
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Treatment Research	000	1	9/2/2022	NEW	$449,487
														Subtotal = $545,024

Grand Total All Awards = $2,092,135

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Therapeutic targeting of IRAK4 in MDS

Award Number: R01CA275007

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer