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Acute Myeloid Leukemia
The chromatin-remodeling factor CHD4 is required for maintenance of childhood acute myeloid leukemia
Yaser Heshmati,1 Gözde Türköz,1 Aditya Harisankar,1 Shabnam Kharazi,2 Johan Boström,3 Esmat Kamali Dolatabadi,1 Aleksandra Krstic,2
David Chang,1 Robert Månsson,2,4 Mikael Altun,3 Hong Qian1
and Julian Walfridsson1
1Center for Hematology and Regenerative Medicine, Department of Medicine; 2Center for Hematology and Regenerative Medicine, Department of Laboratory Medicine; 3Research Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, and 4Hematology Center, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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 iden- tify leukemia-specific dependencies. One of the target genes displaying the strongest effects on acute myeloid leukemia cell growth and less pro- nounced effects on nontransformed bone marrow cells, was the chro- matin 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 nor- mal hematopoietic cells. Taken together, our results identified CHD4 as a potential therapeutic target in childhood acute myeloid leukemia.
Introduction
Acute myeloid leukemia (AML) is a stem cell disease, characterized by rare leukemia-initiating cells (LICs) with increased self-renewal capacity that can propagate rapidly, growing immature myeloid blast cells with limited differenti- ation capacity.1,2 The LICs are largely resistant to chemotherapy and therefore many patients will ultimately relapse, which accounts for the leading cause of death in AML.3
The genetic, epigenetic and transcriptomic landscape in AML differs significant- ly between adults and children. Many of the causative lesions identified in adult AML (e.g., IDH1 and DNMT3A mutations) are rare events in childhood AML, whereas other gene mutations are more frequent in childhood AML (e.g., MYC, IKFZ1 and EZH2).4,5 The molecular differences between adult and childhood AML also include alterations in chromosomal copy number, translocations, different micro ribonucleic acid (miRNA) and messenger (m)RNA expression levels as well as epigenetic patterns.4 For example, translocations involving the MLL gene com- prise 15% to 20% of all childhood acute myeloid leukemia (AML) cases. In con- trast, only around 5% of adult AML patients carry MLL-rearrangements.6 These differences manifest as dissimilar biological characteristics, clinical behavior and different response to treatment.7
Ferrata Storti Foundation
Haematologica 2018 Volume 103(7):1169-1181
Correspondence:
julian.walfridsson@ki.se
Received: November 7, 2017. Accepted: March 23, 2018. Pre-published: March 29, 2018.
doi:10.3324/haematol.2017.183970
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/7/1169
©2018 Ferrata Storti Foundation
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