Therapeutic restoration of CUX1 in -7/DEL(7Q) acute myeloid leukemia
Active Project Grant Awarded Last action
- Award ID
- F31CA314328
- Recipient
-
The University Of Chicago UEI ZUE9HKT2CLC9
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Place of performance
- Chicago, IL 60637, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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).
Quick answers
Who received award F31CA314328?
F31CA314328 was awarded to The University Of Chicago by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F31CA314328 worth?
$50,114 has been obligated on F31CA314328.
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