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Therapeutic restoration of CUX1 in -7/del(7q) acute myeloid leukemia

Award Number: F31CA314328
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/01/2026
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Therapeutic restoration of CUX1 in -7/del(7q) acute myeloid leukemia - PROJECT SUMMARY The complete or partial loss of chromosome 7 [-7/del(7q)] is a recurrent adverse-risk cytogenetic abnormality found in myeloid neoplasms such as acute myeloid leukemia (AML). Our lab has identified CUX1 as a critical 7q encoded tumor suppressor gene that is likely playing a significant role in the pathogenesis of - 7/del(7q). Previous work by our lab has demonstrated that an shRNA mediated knockdown of Cux1 is sufficient to drive myeloid neoplasia and therapy resistance in mice. Restoring Cux1 expression in this model system is sufficient to ameliorate disease following symptom onset, suggesting that increasing CUX1 expression in patients harboring -7/del(7q) may be of therapeutic value. Yet, efforts to therapeutically restore CUX1 expression have been hampered by the field’s lack of knowledge regarding the determinants of CUX1 levels. The overall objective of this proposal is to illuminate novel druggable targets to enable CUX1 restoration in patients harboring -7/del(7q). To this end, I have performed whole-genome CRISPR-Cas9 screens in human AML cell lines expressing a fluorescent CUX1 reporter to identify novel regulators of CUX1 levels. Amongst the hits, I have identified SLC25A1, a gene encoding the mitochondrial citrate transporter, as a top candidate negative regulator of CUX1. Genetic or pharmacologic perturbation of SLC25A1 in human AML cell lines results in a robust upregulation of CUX1 at the protein level, but not the mRNA level. Furthermore, I have found that pharmacologic inhibition of SLC25A1 sensitizes human AML cell lines to the FDA approved agent venetoclax in a CUX1-dependent manner. Previous work has demonstrated that SLC25A1 perturbation leads to an accumulation of reactive oxygen species (ROS) due to a loss in NADPH production downstream of cytosolic citrate metabolism. This data coupled with the presence of other ROS related genes appearing as hits in our screen has led me to hypothesize that SLC25A1 perturbation post-translationally upregulates CUX1 via a ROS-dependent mechanism. Aim 1 will seek to elucidate the mechanism through which SLC25A1 perturbation influences CUX1 levels by characterizing the effect of SLC25A1 inhibition on CUX1 stability, and post-translational modifications. To elucidate whether these changes are mediated by ROS, these experiments will be performed with and without ROS scavengers such as N-acetylcysteine and MitoTEMPO. Aim 2 will focus on determining the therapeutic potential of SLC25A1 inhibition in combination with venetoclax for the treatment of -7/del(7q) myeloid neoplasia by treating primary patient samples and patient-derived xenograft models. Together, these data will elucidate a novel CUX1 regulatory axis with therapeutic potential for high-risk myeloid neoplasms harboring -7/del(7q).


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: 2026 ( Subtotal = $50,114 )
2026	2026	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Cancer Research Manpower	000	1	5/19/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Therapeutic restoration of CUX1 in -7/del(7q) acute myeloid leukemia

Award Number: F31CA314328

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/01/2026

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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