Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

Laura Hinze; Maren Pfirrmann; Salmaan Karim; James Degar; Connor McGuckin; Divya Vinjamur; Joshua Sacher; Kristen E Stevenson; Donna S Neuberg; Esteban Orellana; Martin Stanulla; Richard I Gregory; Daniel E Bauer; Florence F Wagner; Kimberly Stegmaier; Alejandro Gutierrez

doi:10.1016/j.ccell.2019.03.004

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

Cancer Cell. 2019 Apr 15;35(4):664-676.e7. doi: 10.1016/j.ccell.2019.03.004.

Authors

Laura Hinze¹, Maren Pfirrmann², Salmaan Karim², James Degar², Connor McGuckin², Divya Vinjamur², Joshua Sacher³, Kristen E Stevenson⁴, Donna S Neuberg⁴, Esteban Orellana⁵, Martin Stanulla⁶, Richard I Gregory⁵, Daniel E Bauer⁷, Florence F Wagner³, Kimberly Stegmaier⁸, Alejandro Gutierrez⁹

Affiliations

¹ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
² Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
³ Stanley Center for Psychiatric Research, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁴ Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02445, USA.
⁵ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Stem Cell Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
⁶ Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover 30625, Germany.
⁷ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA.
⁸ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁹ Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02445, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: alejandro.gutierrez@childrens.harvard.edu.

Abstract

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits glycogen synthase kinase 3 (GSK3)-dependent protein ubiquitination and proteasomal degradation, a catabolic source of asparagine. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3α inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.

Keywords: FBXW7; GSK3; Wnt signaling; acute leukemia; asparaginase; asparagine; drug resistance; proteasomal degradation; protein ubiquitination; synthetic lethality.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Asparaginase / pharmacology*
Cell Death / drug effects
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm*
Glycogen Synthase Kinase 3 beta / antagonists & inhibitors
Glycogen Synthase Kinase 3 beta / metabolism
Humans
Jurkat Cells
Leukemia / drug therapy*
Leukemia / genetics
Leukemia / metabolism
Leukemia / pathology
Male
Mice, Inbred NOD
Mice, Transgenic
Polyethylene Glycols / pharmacology*
Proteasome Endopeptidase Complex / metabolism
Protein Kinase Inhibitors / pharmacology
Protein Stability
Proteolysis
Synthetic Lethal Mutations*
THP-1 Cells
Ubiquitination
Wnt Signaling Pathway / genetics*
Wnt3A Protein / genetics*
Wnt3A Protein / metabolism
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
WNT3A protein, human
Wnt3A Protein
Polyethylene Glycols
pegaspargase
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Proteasome Endopeptidase Complex
Asparaginase

Abstract

Publication types

MeSH terms

Substances

Grants and funding