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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

Combinatorial molecule screening identifies a novel diterpene and the BET inhibitor CPI-203 as differentiation inducers of primary acute myeloid leukemia cells

Author

  • Simon Hultmark
  • Aurélie Baudet
  • Ludwig Schmiderer
  • Pavan Prabhala
  • Sara Palma-Tortosa
  • Carl Sandén
  • Thoas Fioretos
  • Rajkumar Sasidharan
  • Christer Larsson
  • Sören Lehmann
  • Gunnar Juliusson
  • Fredrik Ek
  • Mattias Magnusson
Show all

Summary, in English

Combination treatment has proven effective for patients with acute promyelocytic leukemia, exemplifying the importance of therapy targeting multiple components of oncogenic regulation for a successful outcome. However, recent studies have shown that the mutational complexity of acute myeloid leukemia (AML) precludes the translation of molecular targeting into clinical success. Here as a complement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop personalized combinatorial treatments. First, we screened 513 natural compounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AMLs, while FLT3-ITD/mutations conferred resistance. The responding samples to H4, displayed increased expression of myeloid markers, a clear decrease in the nuclear-cytoplasmic ratio and the potential of re-activation of the monocytic transcriptional program reducing leukemia propagation in vivo. By combinatorial screening using H4 and molecules with defined targets, we demonstrated that H4 induces differentiation by the activation of protein kinase C (PKC) signaling pathway, and in line with this, activates PKC phosphorylation and translocation of PKC to the cell membrane. Furthermore, the combinatorial screening identified a bromo- and extra-terminal domain (BET) inhibitor that could further improve H4-dependent leukemic differentiation in FLT3 wild-type monocytic AML. Taken together, this illustrates the value of an unbiased and multiplex screening platform for developing combinatorial therapeutic approaches for AML.

Department/s

  • Stem cell and Cancer stem cell Regulation
  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • Division of Molecular Medicine and Gene Therapy
  • Neurology, Lund
  • Stem Cells & Restorative Neurology
  • LUCC: Lund University Cancer Centre
  • Translational Genomic and Functional Studies of Leukemia
  • Division of Clinical Genetics
  • Tumor Cell Biology
  • Division of Translational Cancer Research
  • NanoLund: Centre for Nanoscience
  • Chemical Biology and Therapeutics
  • MultiPark: Multidisciplinary research focused on Parkinson´s disease

Publishing year

2021

Language

English

Publication/Series

Haematologica

Volume

106

Issue

10

Document type

Journal article

Publisher

Ferrata Storti Foundation

Topic

  • Hematology
  • Cell and Molecular Biology

Status

Published

Research group

  • Stem cell and Cancer stem cell Regulation
  • Stem Cells & Restorative Neurology
  • Translational Genomic and Functional Studies of Leukemia
  • Tumor Cell Biology
  • Chemical Biology and Therapeutics

ISBN/ISSN/Other

  • ISSN: 1592-8721