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The function of MS4A3 in normal and malignant hematopoiesis

Award Number: R01CA268496
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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The function of MS4A3 in normal and malignant hematopoiesis - Chronic myeloid leukemia (CML) is caused by BCR-ABL1, a constitutively active tyrosine kinase generated from the Philadelphia chromosome. In the chronic phase of CML (CP-CML), myeloid cells are expanded, but maintain terminal differentiation. Most CP-CML patients achieve durable responses to BCR-ABL1 tyrosine kinase inhibitors (TKIs), and their extended survival is reflected by a steep rise in CML prevalence. Unfortunately, TKIs fail to eliminate quiescent CML stem cells (LSCs) whose survival is independent of BCR-ABL1, necessitating lifelong TKI therapy to prevent CML recurrence. In 5-10% of patients, a differentiation block converts CP-CML into blast phase CML (BP-CML), an aggressive acute leukemia that is often BCR-ABL1-independent and TKI resistant. Our overarching hypothesis is that blocked differentiation is central to the BCR-ABL1 independence that characterizes the extremes of the clinical CML spectrum: Persistence of residual leukemia despite TKI therapy and TKI-resistant BP-CML. We have discovered that expression of MS4A3, a member of the MS4A (membrane-spanning four A) family of signaling proteins, is profoundly reduced in quiescent, TKI resistant and BP CML cells, and that low MS4A3 correlates with shorter survival. MS4A3 knockdown (KD) in CML CD34+ cells inhibits myeloid differentiation, and promotes TKI resistance, while ectopic MS4A3 expression has opposite effects (Zhao et al. Blood. 2021;Epub ahead of print. PMID: 34780648). Our preliminary data suggest that MS4A3 promotes IL-3 and GM-CSF signaling in CML CD34+ cells by promoting endocytosis of their cognate β common chain (βc) receptors. We hypothesize that MS4A3 promotes myeloid differentiation by enhancing response to βc cytokines in leukemic stem and progenitor cells (LSPCs). TKI resistant CML cells downregulate MS4A3 to blunt response to differentiation-inducing cytokines, thereby maintaining a primitive, therapy-resistant state. Re- establishment of MS4A3 expression will enforce differentiation and enhance drug sensitivity. In Aim 1, we will delineate how MS4A3 regulates endocytosis and signaling of βc cytokine receptors. We will track endocytosis by high-throughput immunofluorescent and confocal live cell imaging, identify MS4A3 cofactors by mass spectrometry, and MS4A3-regulated signaling pathways by reverse phase protein array. In Aim 2, we will determine the function of MS4A3 in normal hematopoiesis. We will generate mouse strains with hematopoietic- specific conditional Ms4a3 knockout or inducible overexpression and characterize their hematopoietic system at steady state and under stress. In Aim 3, we will delineate the role of MS4A3 in CML hematopoiesis and as a therapeutic agent in CML. We will test whether modulating MS4A3 expression in LSPCs affects leukemogenesis and TKI response, and whether MS4A3-loaded nanoparticles attenuate BP-CML in xenografts. If successful, we will establish MS4A3 as a novel master regulator of βc cytokine signaling that governs signal strength by modulating endocytosis. BP-CML remains mostly incurable, and most CP-CML patients require lifelong TKI therapy. Our work may provide proof of concept for using forced MS4A3 expression to overcome TKI resistance.


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 = $473,053 )
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Biology Research	001	3	9/18/2025	NON-COMPETING CONTINUATION	$47,304
2025	2025	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Biology Research	000	3	3/5/2025	NON-COMPETING CONTINUATION	$425,749
														Subtotal = $473,053

Issue Date FY: 2024 ( Subtotal = $592,404 )
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Biology Research	001	2	4/17/2024	NON-COMPETING CONTINUATION	$31,180
2024	2024	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Biology Research	000	2	12/21/2023	NON-COMPETING CONTINUATION	$561,224
														Subtotal = $592,404

Issue Date FY: 2023 ( Subtotal = $466,620 )
2023	2023	VERSITI WISCONSIN, INC.	638 N 18TH ST	MILWAUKEE	WI	53233	MILWAUKEE	USA	Cancer Biology Research	000	1	12/30/2022	NEW	$466,620
														Subtotal = $466,620

Grand Total All Awards = $1,532,077

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The function of MS4A3 in normal and malignant hematopoiesis

Award Number: R01CA268496

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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