Journal article
Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade
Blood, Vol.139(26), pp.3752-3770
06/30/2022
DOI: 10.1182/blood.2021015108
PMCID: PMC9247363
PMID: 35439288
Abstract
Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERIC) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy.
Details
- Title: Subtitle
- Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade
- Creators
- Hanying Wang - City Of Hope National Medical CenterXin He - City Of Hope National Medical CenterLei Zhang - City Of Hope National Medical CenterHaojie Dong - City Of Hope National Medical CenterFeiteng Huang - City Of Hope National Medical CenterJie Xian - City Of Hope National Medical CenterMin Li - City Of Hope National Medical CenterWei Chen - City Of Hope National Medical CenterXiyuan Lu - The University of Texas at AustinKhyatiben Pathak - Translational Genomics Research InstituteWenfeng Huang - City Of Hope National Medical CenterZheng Li - City Of Hope National Medical CenterLianjun Zhang - City Of Hope National Medical CenterLe Xuan Truong Nguyen - City Of Hope National Medical CenterLu Yang - City Of Hope National Medical CenterLifeng Feng - Sir Run Run Shaw HospitalDavid J. Gordon - University of IowaJing Zhang - University of Wisconsin–MadisonPatrick Pirrotte - City Of Hope National Medical CenterChun-Wei Chen - City Of Hope National Medical CenterAmandeep Salhotra - City Of Hope National Medical CenterYa-Huei Kuo - City Of Hope National Medical CenterDavid Horne - City Of Hope National Medical CenterGuido Marcucci - City Of Hope National Medical CenterDavid B. Sykes - Massachusetts General HospitalStefano Tiziani - The University of Texas at AustinHongchuan Jin - Sir Run Run Shaw HospitalXian Wang - Sir Run Run Shaw HospitalLing Li - City Of Hope National Medical Center
- Resource Type
- Journal article
- Publication Details
- Blood, Vol.139(26), pp.3752-3770
- DOI
- 10.1182/blood.2021015108
- PMID
- 35439288
- PMCID
- PMC9247363
- NLM abbreviation
- Blood
- ISSN
- 0006-4971
- eISSN
- 1528-0020
- Publisher
- Amer Soc Hematology
- Number of pages
- 19
- Grant note
- CA190124 / Department of Defense; United States Department of Defense Gehr Family Center for Leukemia Research R01 CA2062101 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01 CA152108 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA DP150061 / Cancer Prevention & Research Institute of Texas P30CA33572 / Animal Resources Center, Analytical Cytometry Core, Bioinformatics, Light Microscopy, Electron Microscopy, Integrative Genomics Core, Mass Spectrometry & Proteomic Core at COH Comprehensive Cancer Center - NIH, National Cancer Institute
- Language
- English
- Date published
- 06/30/2022
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984353829502771
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