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Functional characterization of CUX1 regulators for the treatment of myelodysplastic syndromes

Award Number: F32HL156600
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Functional characterization of CUX1 regulators for the treatment of myelodysplastic syndromes - PROJECT SUMMARY/ABSTRACT The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders characterized by cytopenias and dysplasia in one or more of the myeloid cell lines due to ineffective hematopoiesis. Patients present with signs and symptoms of anemia, accompanied by infections and bleeding leading to serious morbidity. Loss of chromosome 7 (-7) or the long-arm of 7 [del(7q)] is commonly seen in high-risk MDS patients. Treatment options are limited and high-risk patients have less than one-year survival. Cut-like homeobox 1 (CUX1), a transcription factor encoded in the commonly deleted segment of 7q22, is expressed at haploinsufficient transcript and protein levels in -7/del(7q) myeloid diseases. Knockdown of CUX1 causes a spontaneous hematopoietic disorder with many features of human MDS, including erythroid dysplasia, and fatal anemia, indicating that loss of this single gene is sufficient to cause disease. Remarkably, CUX1 re-expression reverses MDS in mice, which provides the premise for the current proposal, that restoration of CUX1 is a viable therapeutic strategy for MDS patients. However, there exists a major gap in our understanding of the mechanisms by which CUX1 levels are regulated. Preliminary studies indicate that Glycogen synthase kinase- 3 (GSK3) inhibition increases cellular CUX1 protein levels. The central hypothesis is that pharmacological induction of CUX1 levels will restore hematopoietic stem cell homeostasis and reverse impaired differentiation in CUX1 deficient myeloid disease models. The central hypothesis will be tested by pursuing two specific aims: 1) define the cellular and molecular mechanisms by which CUX1 levels are regulated, and 2) drive normal erythroid differentiation of -7/del(7q) myelodysplasia through therapeutic restoration of CUX1. Under the first aim, GSK3 mediated post-translational regulatory mechanism of CUX1 levels will be determined using site- directed mutational analysis in immortalized human blood cell lines. Additionally, a genome-wide CRISPR/Cas9 loss of function screen will be utilized to identify novel regulators of CUX1. For the second aim, CD34+ human -7/del(7q) MDS cells and CUX1-deficient mouse models will be used to determine the efficacy of GSK3 isoform selective inhibitors in restoring CUX1 protein and reversing erythroid differentiation defects. The proposed research is expected to reveal druggable and regulatory pathways of CUX1 to restore its levels as a way of reversing anemia and dysplasia in -7/del(7q) MDS 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 = $81,892 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	3	11/6/2023	NON-COMPETING CONTINUATION	$76,272
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	001	3	8/29/2024	NON-COMPETING CONTINUATION	$5,620
														Subtotal = $81,892

Issue Date FY: 2023 ( Subtotal = $74,292 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	2	11/9/2022	NON-COMPETING CONTINUATION	$72,302
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	001	2	3/31/2023	NON-COMPETING CONTINUATION	$1,990
														Subtotal = $74,292

Issue Date FY: 2021 ( Subtotal = $68,890 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	000	1	9/15/2021	NEW	$68,890
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Blood Diseases and Resources Research	001	1	9/15/2021	NEW	$0
														Subtotal = $68,890

Grand Total All Awards = $225,074

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Functional characterization of CUX1 regulators for the treatment of myelodysplastic syndromes

Award Number: F32HL156600

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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