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

Hanying Wang1,2, Xin He1, Lei Zhang1

  • 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.

Blood
|April 19, 2022
PubMed

Insights

Hyperactivating ribonucleotide reductase (RNR) promotes acute myeloid leukemia (AML) cell differentiation and growth reduction. This unexpected finding in AML treatment offers a new therapeutic strategy by targeting RNR and dNTP homeostasis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Hematology

Background:

  • Acute myeloid leukemia (AML) is characterized by differentiation blockade, hindering effective treatment strategies.
  • Dysregulated ribonucleotide reductase (RNR) is a potential therapeutic target in cancers sensitive to deoxynucleoside triphosphate (dNTP) depletion.

Purpose of the Study:

  • To investigate the role of RNR in AML differentiation and identify novel therapeutic strategies.
  • To elucidate the mechanisms by which RNR hyperactivation impacts leukemia cell growth and differentiation.

Main Methods:

  • Integrated pharmacogenomic and metabolomic analyses to study RNR subunit M2 (RRM2) upregulation.
  • Investigated R-loop-mediated DNA replication stress signaling and its role in RRM2 activation.
  • Utilized CRISPR screening to identify synthetic lethal interactions with nelarabine treatment.

Main Results:

  • Pharmacological or genetic upregulation of RRM2 induces dNTP pool imbalance, overcoming differentiation arrest in AML.
  • Nelarabine treatment activates RRM2 via R-loop-mediated DNA replication stress signaling.
  • Depleting SAMHD1 enhances RRM2-mediated ablation of leukemia stem cells, and ERK signaling activation contributes to these outcomes.
  • A synthetic lethal interaction between DUSP6 loss and nelarabine treatment was identified.

Conclusions:

  • Deoxynucleoside triphosphate (dNTP) homeostasis is critical for leukemia maintenance.
  • Hyperactivating RNR represents a promising strategy to induce differentiation and reduce leukemia cell growth.
  • Combining DUSP inhibition with nelarabine offers a potential therapeutic approach for AML.

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