The chromatin-remodeling factor CHD4 is required for maintenance of childhood acute myeloid leukemia
EHA Learning Center. Heshmati Y. Jul 1, 2018; 224109
Topic: 2B Acute myeloid leukemia (AML) and leukemias of ambiguous lineage
Yaser Heshmati
Yaser Heshmati
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Co-Authors: Gözde Türköz, Aditya Harisankar, Shabnam Kharazi, Johan Boström, Esmat Kamali Dolatabadi, Aleksandra Krstic, David Chang, Robert Månsson, Mikael Altun, Hong Qian, Julian Walfridsson

Abstract: Epigenetic alterations contribute to leukemogenesis in childhood acute myeloid leukemia and therefore are of interest for potential therapeutic strategies. Herein, we performed large-scale ribonucleic acid interference screens using small hairpin ribonucleic acids in acute myeloid leukemia cells and non-transformed bone marrow cells to identify leukemia-specific dependencies. One of the target genes displaying the strongest effects on acute myeloid leukemia cell growth and less pronounced effects on nontransformed bone marrow cells, was the chromatin remodeling factor CHD4. Using ribonucleic acid interference and CRISPR-Cas9 approaches, we showed that CHD4 was essential for cell growth of leukemic cells in vitro and in vivo. Loss of function of CHD4 in acute myeloid leukemia cells caused an arrest in the G0 phase of the cell cycle as well as downregulation of MYC and its target genes involved in cell cycle progression. Importantly, we found that inhibition of CHD4 conferred anti-leukemic effects on primary childhood acute myeloid leukemia cells and prevented disease progression in a patient-derived xenograft model. Conversely, CHD4 was not required for growth of normal hematopoietic cells. Taken together, our results identified CHD4 as a potential therapeutic target in childhood acute myeloid leukemia.

Article Number: 1169

Doi: 10.3324/haematol.2017.183970

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