TY - JOUR
T1 - Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia
AU - Wiggers, Caroline R M
AU - Govers, Anita M A P
AU - Lelieveld, Daphne
AU - Egan, David A
AU - Zwaan, C Michel
AU - Sonneveld, Edwin
AU - Coffer, Paul J
AU - Bartels, Marije
N1 - Funding Information:
informationThis research was supported by the Foundation Friends of the UMC Utrecht/Wilhelmina Children's Hospital and Dutch Cancer Society (DSC, Grant Number: 4855).We would like to thank Constantin Rohde and Stephin Vervoort for their effort in setting up the 80-compound screen. Also, we would like to thank Maarten Fornerod for providing the pediatric AML cell lines THP-1 and Kasumi-1.
Funding Information:
This research was supported by the Foundation Friends of the UMC Utrecht/Wilhelmina Children’s Hospital and Dutch Cancer Society (DSC, Grant Number: 4855).
Publisher Copyright:
© 2019 Wiley Periodicals, Inc.
PY - 2019/8
Y1 - 2019/8
N2 - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment-related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed.PROCEDURE: To identify potential novel therapeutic targets for myeloid disorders in children, including DS-AMKL and non-DS-AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre-)leukemic pediatric patient cells.RESULTS: Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan-histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation.CONCLUSION: NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS-AMKL.
AB - BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease regarding morphology, immunophenotyping, genetic abnormalities, and clinical behavior. The overall survival rate of pediatric AML is 60% to 70%, and has not significantly improved over the past two decades. Children with Down syndrome (DS) are at risk of developing acute megakaryoblastic leukemia (AMKL), which can be preceded by a transient myeloproliferative disorder during the neonatal period. Intensification of current treatment protocols is not feasible due to already high treatment-related morbidity and mortality. Instead, more targeted therapies with less severe side effects are highly needed.PROCEDURE: To identify potential novel therapeutic targets for myeloid disorders in children, including DS-AMKL and non-DS-AML, we performed an unbiased compound screen of 80 small molecules targeting epigenetic regulators in three pediatric AML cell lines that are representative for different subtypes of pediatric AML. Three candidate compounds were validated and further evaluated in normal myeloid precursor cells during neutrophil differentiation and in (pre-)leukemic pediatric patient cells.RESULTS: Candidate drugs LMK235, NSC3852, and bromosporine were effective in all tested pediatric AML cell lines with antiproliferative, proapoptotic, and differentiation effects. Out of these three compounds, the pan-histone deacetylase inhibitor NSC3852 specifically induced growth arrest and apoptosis in pediatric AML cells, without disrupting normal neutrophil differentiation.CONCLUSION: NSC3852 is a potential candidate drug for further preclinical testing in pediatric AML and DS-AMKL.
KW - DS-AMKL
KW - HDACi
KW - NSC3852
KW - epigenetic treatment
KW - pediatric AML
KW - Cell Proliferation
KW - Prognosis
KW - Epigenesis, Genetic
KW - Humans
KW - Leukemia, Myeloid, Acute/drug therapy
KW - Hydroxyquinolines/pharmacology
KW - Leukemia, Megakaryoblastic, Acute/drug therapy
KW - Histone Deacetylases/chemistry
KW - Leukemoid Reaction/drug therapy
KW - High-Throughput Screening Assays
KW - Down Syndrome/drug therapy
KW - Drug Screening Assays, Antitumor/methods
KW - Nitroso Compounds/pharmacology
KW - Histone Deacetylase Inhibitors/pharmacology
KW - Tumor Cells, Cultured
KW - Child
KW - Apoptosis
UR - http://www.scopus.com/inward/record.url?scp=85065245896&partnerID=8YFLogxK
U2 - 10.1002/pbc.27785
DO - 10.1002/pbc.27785
M3 - Article
C2 - 31044544
SN - 1545-5009
VL - 66
JO - Pediatric Blood & Cancer
JF - Pediatric Blood & Cancer
IS - 8
M1 - e27785
ER -