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

Hultmark, Simon LU ; Baudet, Aurélie LU ; Schmiderer, Ludwig LU ; Prabhala, Pavan LU ; Palma-Tortosa, Sara LU ; Sandén, Carl LU ; Fioretos, Thoas LU ; Sasidharan, Rajkumar ; Larsson, Christer LU and Lehmann, Sören , et al. (2020) In Haematologica
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Haematologica
publisher
Ferrata Storti Foundation
external identifiers
  • pmid:32855276
ISSN
1592-8721
DOI
10.3324/haematol.2020.249177
language
English
LU publication?
yes
additional info
Copyright © 2020, Ferrata Storti Foundation.
id
3a452712-d803-4a32-89e9-a9290f139572
date added to LUP
2020-09-01 16:38:55
date last changed
2020-10-01 18:44:10
@article{3a452712-d803-4a32-89e9-a9290f139572,
  abstract     = {<p>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.</p>},
  author       = {Hultmark, Simon and Baudet, Aurélie and Schmiderer, Ludwig and Prabhala, Pavan and Palma-Tortosa, Sara and Sandén, Carl and Fioretos, Thoas and Sasidharan, Rajkumar and Larsson, Christer and Lehmann, Sören and Juliusson, Gunnar and Ek, Fredrik and Magnusson, Mattias},
  issn         = {1592-8721},
  language     = {eng},
  month        = {08},
  publisher    = {Ferrata Storti Foundation},
  series       = {Haematologica},
  title        = {Combinatorial molecule screening identifies a novel diterpene and the BET inhibitor CPI-203 as differentiation inducers of primary acute myeloid leukemia cells},
  url          = {http://dx.doi.org/10.3324/haematol.2020.249177},
  doi          = {10.3324/haematol.2020.249177},
  year         = {2020},
}