Premium
Epigenetic drug screen identifies the histone deacetylase inhibitor NSC3852 as a potential novel drug for the treatment of pediatric acute myeloid leukemia
Author(s) -
Wiggers Caroline R.M.,
Govers Anita M.A.P.,
Lelieveld Daphne,
Egan David A.,
Zwaan C. Michel,
Sonneveld Edwin,
Coffer Paul J.,
Bartels Marije
Publication year - 2019
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.27785
Subject(s) - medicine , myeloid leukemia , acute megakaryoblastic leukemia , myeloid , histone deacetylase inhibitor , immunophenotyping , histone deacetylase , oncology , cancer research , leukemia , down syndrome , immunology , pharmacology , histone , biology , antigen , psychiatry , biochemistry , gene
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.