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Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2566-2577
Combinatorial molecule screening identified a novel diterpene and the BET inhibitor CPI-203 as differentiation inducers of primary acute myeloid leukemia cells
Simon Hultmark,1 Aurélie Baudet,1,2 Ludwig Schmiderer,1 Pavan Prabhala,1 Sara Palma-Tortosa,3 Carl Sandén,4 Thoas Fioretos,4 Rajkumar Sasidharan,5 Christer Larsson,6 Sören Lehmann,7,8 Gunnar Juliusson,2,9 Fredrik Ek10# and Mattias Magnusson1#
1Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden; 2Division of Molecular Hematology, Lund Stem Cell Center, Lund University, Lund, Sweden; 3Laboratory of Stem Cells and Restorative Neurology, Lund Stem Cell Center, Lund University, Lund, Sweden; 4Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden; 5Solvuu, Inc., New York, NY, USA; 6Division of Translational Cancer Research, Lund University, Lund, Sweden; 7Department of Medical Sciences, Uppsala University Hospital, Uppsala, Sweden; 8Department of Medicine, Karolinska Institute, Stockholm, Sweden; 9Department of Hematology, Skane University Hospital, Lund, Sweden and 10Chemical Biology & Therapeutics, Lund University, Lund, Sweden.
#FE and MM contributed equally as co-senior authors.
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 com- plement to genetic profiling, we used unbiased, combinatorial in vitro drug screening to identify pathways that drive AML and to develop per- sonalized combinatorial treatments. First, we screened 513 natural com- pounds on primary AML cells and identified a novel diterpene (H4) that preferentially induced differentiation of FLT3 wild-type AML, while FLT3-ITD/mutations conferred resistance. The samples responding 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 activa- tion of the 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. These findings illustrate the value of an unbiased, multiplex screening platform for developing combinatorial therapeutic approaches for AML.
Introduction
Acute myeloid leukemia (AML) is the most common form of adult acute leukemia. It is characterized by the accumulation of immature myeloid cells with increased self-renewal, apoptotic resistance and dysfunctional differentiation leading to subsequent infections, anemia and bleeding.1 Although the majority of patients initially respond to the standard of care (cytotoxic chemotherapy), a substantial number of patients will relapse with a 10-year survival of only 20%
Acute Myeloid Leukemia
Correspondence:
MATTIAS MAGNUSSON
mattias.magnusson@med.lu.se
Received: February 17, 2020. Accepted: August 25, 2020. Pre-published: August 27, 2020.
https://doi.org/10.3324/haematol.2020.249177 ©2021 Ferrata Storti Foundation
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