Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

Authors

Institutions

Publication Details

Journal
HemaSphere
Published
2024-11-28
DOI
https://doi.org/10.1002/hem3.70001
Citations
6
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
2.73

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

Elizabeth Heyes, Peter Valent, Elvin D. de Araujo, Heidi A. Neubauer et al.
6 citations
HemaSphere
Acute Myeloid Leukemia Research
2.73
article

Dual specific STAT3/5 degraders effectively block acute myeloid leukemia and natural killer/T cell lymphoma

Elizabeth Heyes, Peter Valent, Elvin D. de Araujo, Heidi A. Neubauer, Satu M. Mustjoki, Christine Pirker, Richard Moriggl, Tero A. Aittokallio, Diaaeldin I. Abdallah, Maik Dahlhoff, Sanna Timonen, Thomas Eder, Emir Hadzijusufovic, Marco Herling, Patrick T. Gunning, Marta Surbek, Walter Berger, Michael Bergmann, Lukas Kenner, Daniel Pölöske, Heikki Kuusanmäki, Aleksandr Ianevski, Roman Fleck, Anna Schönbichler, Wolfgang R. Sperr, Martin Metzelder, Anna Orlova, Helena Sorger, Florian Grebien, Christina Wagner, Tobias Suske
article en
6 citations

Abstract

The transcription factors STAT3, STAT5A, and STAT5B steer hematopoiesis and immunity, but their enhanced expression and activation promote acute myeloid leukemia (AML) or natural killer/T cell lymphoma (NKCL). Current therapeutic strategies focus on blocking upstream tyrosine kinases to inhibit STAT3/5, but these kinase blockers are not selective against STAT3/5 activation and frequent resistance causes relapse, emphasizing the need for targeted drugs. We evaluated the efficacy of JPX-0700 and JPX-0750 as dual STAT3/5 binding inhibitors promoting protein degradation. JPX-0700/-0750 decreased the mRNA and protein levels of STAT3/5 targets involved in cancer survival, metabolism, and cell cycle progression, exhibiting nanomolar to low micromolar efficacy. They induced cell death and growth arrest in both AML/NKCL cell lines and primary AML patient blasts. We found that both AML/NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in kinases, activating mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative, or epigenetic-modifying STAT3/5 targets. This emphasizes a vicious cycle for proliferation and survival through STAT3/5. Both JPX-0700/-0750 treatment reduced leukemic cell growth in human AML or NKCL xenograft mouse models significantly, being well tolerated by mice. Synergistic cell death was induced upon combinatorial use with approved chemotherapeutics in AML/NKCL cells.

HemaSphereVol. 8(12)
University of Copenhagen (DK), University of Helsinki (FI), University of Veterinary Medicine Vienna (AT), University of Salzburg (AT), University of Oslo (NO), University of Toronto (CA), Helsinki University Hospital (FI), Vienna General Hospital (AT), Comprehensive Cancer Center Vienna (AT), Christian Doppler Laboratory for Thermoelectricity (AT), St Anna Children's Hospital (AT), Center For Biomarker Research In Medicine (AT), Institute for Molecular Medicine Finland (FI), Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE), Cancer Society of Finland (FI), St. Anna Children's Cancer Research Institute, Medical University of Vienna (AT), Umeå University (SE), Leipzig University (DE)
Siemens Medical Solutions USA, European Commission, Vienna Science and Technology Fund, Austrian Science Fund, Universität Wien, Medizinische Universität Wien, Christian Doppler Forschungsgesellschaft, Veterinärmedizinische Universität Wien
Good health and well-being
Openalex Percentile: Top 9%
Acute Myeloid Leukemia Research
2.73
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.