Summary of project PR001798
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001798. The data can be accessed directly via it's Project DOI: 10.21228/M89D97 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001798 |
| Project DOI: | doi: 10.21228/M89D97 |
| Project Title: | High Level Expression of NSD2 Creates a Metabolic Dependency in Multiple Myeloma |
| Project Summary: | Multiple myeloma (MM) is a malignancy of plasma cells with several molecular subtypes and variable prognosis. Despite therapeutic advances, most patients ultimately relapse due to drug resistance. Frontline treatments for MM target malignant cells based on their differentiated B cell nature, but not the underlying genetic lesions. Chromosomal translocation t(4;14), observed in 15% of MM patients, results in overexpression of the histone methyltransferase NSD2, which contributes to MM pathogenesis by promoting an oncogenic transcriptional program and is associated with a worse prognosis. A genome-wide CRISPR based functional screen in isogenic MM cell lines with high and low NSD2 expression identified the mitochondrial enzyme adenylate kinase 2 (AK2) as a NSD2-driven MM cell dependency. AK2 loss in t(4;14) MM cells induced apoptosis and inhibited cell growth in vitro and in vivo. Consistent with a defect in shuttling ATP from the mitochondria to intracellular utilization sites, AK2 depletion impaired ATP-dependent protein folding in the ER and increased MM cell sensitivity to the proteasome inhibitor bortezomib. Furthermore, AK2 suppression decreased intracellular NAD(H) phosphorylation resulting in lower NADP(H) levels. Cytosolic NADPH is necessary for reducing thioredoxin, an essential cofactor for ribonucleotide reductase which is critical for deoxyribonucleotides (dNTP) synthesis. Consequently, AK2 deficiency in MM cells resulted in dNTP pool depletion and induced DNA replication stress. Creatine phosphorylation by mitochondrial creatine kinase is an alternative route for shuttling ATP from the mitochondria to the cytosol. Metabolomics analysis revealed decreased levels of creatine and accumulation of its precursor guanadoacetate in NSD2 high cells, in association with elevated levels of S-adenosyl homocysteine (SAH) indicating consumption of the carbon donor S-Adenosyl methionine (SAM). This along with the 6-fold increase in genome wide H3K36me2 levels and 40% increase in DNA methylation levels in NSD2 high cells suggested that overexpression of NSD2 redirected one-carbon metabolism to the epigenome and away from the SAM-dependent creatine synthesis. Therefore, decreased creatine levels in NSD2 overexpressing cells underlie the increased reliance on AK2. Correspondingly, supplementation with exogenous creatine restored NADP(H) levels and rescued AK2 deficient cells from apoptosis. These findings revealed a novel metabolic susceptibility in t(4;14) MM and provided insight into a novel therapeutic strategy to improve patient prognosis. |
| Institute: | Northwestern University |
| Last Name: | Licht |
| First Name: | Jonathan |
| Address: | 2033 MOWRY RD STE 145 GAINESVILLE FL 32610 |
| Email: | jdlicht@ufl.edu |
| Phone: | (352) 273-8143 |
Summary of all studies in project PR001798
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST002876 | High Level Expression of NSD2 Creates a Metabolic Dependency in Multiple Myeloma | Homo sapiens | University of Florida | MS | 2023-10-30 | 1 | 18 | Uploaded data (1.4G)* |
