Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade

Author:

Wang Hanying12,He Xin1,Zhang Lei1,Dong Haojie1,Huang Feiteng13,Xian Jie1,Li Min4,Chen Wei5,Lu Xiyuan6,Pathak Khyatiben V.7,Huang Wenfeng1,Li Zheng18,Zhang Lianjun1,Nguyen Le Xuan Truong1,Yang Lu9,Feng Lifeng10,Gordon David J.11,Zhang Jing12,Pirrotte Patrick713ORCID,Chen Chun-Wei9ORCID,Salhotra Amandeep14,Kuo Ya-Huei1ORCID,Horne David15,Marcucci Guido114,Sykes David B.16,Tiziani Stefano61718ORCID,Jin Hongchuan10,Wang Xian2,Li Ling1

Affiliation:

1. 1Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, Hematologic Malignancies and Stem Cell Transplantation Institute, Beckman Research Institute, City of Hope Medical Center, Duarte, CA;

2. 2Department of Medical Oncology and

3. 3Department of Hematology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China;

4. 4Department of Information Sciences, Beckman Research Institute and

5. 5Integrative Genomics Core, Beckman Research Institute, City of Hope Medical Center, Duarte, CA;

6. 6Department of Nutritional Sciences, The University of Texas at Austin, Austin, TX;

7. 7Cancer & Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ;

8. 8Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China;

9. 9Department of Systems Biology, Beckman Research Institute, City of Hope Medical Center, Duarte, CA;

10. 10Laboratory of Cancer Biology, Provincial Key Laboratory of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China;

11. 11Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Iowa, Iowa City, IA;

12. 12McArdle Laboratory for Cancer Research and Wisconsin Blood Cancer Research Institute, University of Wisconsin-Madison, Madison, WI;

13. 13Cancer & Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ;

14. 14Department of Hematology and Hematopoietic Cell Transplantation and

15. 15Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA;

16. 16Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA; and

17. 17Department of Pediatrics and

18. 18Department of Oncology, Dell Medical School, LiveSTRONG Cancer Institutes, The University of Texas at Austin, Austin, TX

Abstract

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 (ERK) 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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