The chromatin-remodeling factor CHD4 is required for maintenance of childhood acute myeloid leukemia

• Published in: Haematologica (Roma) Vol. 103; no. 7; pp. 1169 - 1181
• Main Authors: Heshmati, Yaser, Türköz, Gözde, Harisankar, Aditya, Kharazi, Shabnam, Boström, Johan, Dolatabadi, Esmat Kamali, Krstic, Aleksandra, Chang, David, Månsson, Robert, Altun, Mikael, Qian, Hong, Walfridsson, Julian
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01-07-2018
• Subjects: Medicin och hälsovetenskap
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2017.183970

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
Using ribonucleic acid interference and CRISPR-Cas9 approaches, we showed that
was essential for cell growth of leukemic cells
and
Loss of function of
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
conferred anti-leukemic effects on primary childhood acute myeloid leukemia cells and prevented disease progression in a patient-derived xenograft model. Conversely,
was not required for growth of normal hematopoietic cells. Taken together, our results identified
as a potential therapeutic target in childhood acute myeloid leukemia.