Author:
Lalonde Marie-Eve,Sasseville Marc,Gélinas Anne-Marie,Milanese Jean-Sébastien,Béland Kathie,Drouin Simon,Haddad Elie,Marcotte Richard
Abstract
Acute lymphoblastic leukemia (ALL) is the most frequent cancer diagnosed in children. Despite the great progress achieved over the last 40 years, with cure rates now exceeding 85%, refractory or relapsed ALL still exhibit a dismal prognosis. This poor outcome reflects the lack of treatment options specifically targeting relapsed or refractory ALL. In order to address this gap, we performed whole-genome CRISPR/Cas drop-out screens on a panel of seven B-ALL cell lines. Our results demonstrate that while there was a significant overlap in gene essentiality between ALL cell lines and other cancer types survival of ALL cell lines was dependent on several unique metabolic pathways, including an exquisite sensitivity to GPX4 depletion and ferroptosis induction. Detailed molecular analysis of B-ALL cells suggest that they are primed to undergo ferroptosis as they exhibit high steady-state oxidative stress potential, a low buffering capacity, and a disabled GPX4-independent secondary lipid peroxidation detoxification pathway. Finally, we validated the sensitivity of BALL to ferroptosis induction using patient-derived B-ALL samples.
Publisher
Ferrata Storti Foundation (Haematologica)
Reference58 articles.
1. Sabattini E, Bacci F, Sagramoso C, Pileri SA. WHO classification of tumours of haematopoietic and lymphoid tissues in 2008: an overview. Pathologica. 2010; 102(3):83-87.
2. Ellison LF, De P, Mery LS, Grundy PE. for the Canadian Cancer Society’s Steering Committee for Canadian Cancer Statistics. Canadian cancer statistics at a glance: cancer in children. Can Med Assoc J. 2009; 180(4):422-424.
3. Vrooman LM, Silverman LB. Treatment of childhood acute lymphoblastic leukemia: prognostic factors and clinical advances. Curr Hematol Malig Rep. 2016; 11(5):385-394.
4. Bruzzi P, Bigi E, Predieri B. Long-term effects on growth, development, and metabolism of ALL treatment in childhood. Expert Rev Endocrinol Metab. 2019; 14(1):49-61.
5. Meyers RM, Bryan JG, McFarland JM. Computational correction of copy number effect improves specificity of CRISPR–Cas9 essentiality screens in cancer cells. Nat Genet. 2017; 49(12):1779-1784.
Cited by
5 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献