Targeting serine hydroxymethyltransferases 1 and 2 for T-cell acute lymphoblastic leukemia therapy
Year: 2021
Type: article
Abstract: Despite progress in the treatment of acute lymphoblastic leukemia (ALL), T-cell ALL (T-ALL) has limited treatment options, particularly in the setting of relapsed/refractory disease. Using an unbiased genome-scale CRISPR-Cas9 screen we sought to identify pathway dependencies for T-ALL which could be harnessed for therapy development. Disruption of the one-carbon folate, purine and pyrimidine pathways scored as the top metabolic pathways required for T-ALL proliferation. We used a recently developed inhibitor of SHMT1 and SHMT2, RZ-2994, to characterize the effect of inhibiting these enzymes of the one-carbon folate pathway in T-ALL and found that T-ALL cell lines were differentially sensitive to RZ-2994, with the drug inducing a S/G2 cell cycle arrest. The effects of SHMT1/2 inhibition were rescued by formate supplementation. Loss of both SHMT1 and SHMT2 was necessary for impaired growth and cell cycle arrest, with suppression of both SHMT1 and SHMT2 inhibiting leukemia progression in vivo. RZ-2994 also decreased leukemia burden in vivo and remained effective in the setting of methotrexate resistance in vitro. This study highlights the significance of the one-carbon folate pathway in T-ALL and supports further development of SHMT inhibitors for treatment of T-ALL and other cancers.
Source: Leukemia
Institutions: Boston Children's Hospital, Dana-Farber Cancer Institute, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Broad Institute, Boston University, Harvard University, Massachusetts Institute of Technology, Inserm, Hôpital Saint-Louis, University of Parma, Whitehead Institute for Biomedical Research, Dana-Farber/Harvard Cancer Center
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,480
Funders: Howard Hughes Medical Institute, Rally Foundation, Bear Necessities Pediatric Cancer Foundation, Associazione Italiana per la Ricerca sul Cancro, Stand Up To Cancer, Ludwig Center for Molecular Oncology, Ludwig Center at Harvard, National Cancer Institute, Hyundai Hope On Wheels, H2020 European Research Council
Awards: The Effect of Serine Source on Nucleotide Metabolism in Cancer: Manipulating Environmental Nutrient Availability to Impact Tumor Growth, Targeting mitochondrial one carbon folate metabolism for novel T-cell acute lymphoblastic leukemia therapy, G6342997465, G6875477772, In vivo functional screens to decipher mechanisms of stochastically- and mutationally-induced chemoresistance in Acute Myeloid Leukemia, Integrating Transforming Approaches to Identify and Target New Vulnerabilities in Cancer, Cancer Center Support (Core) Grant, Understanding the role of metabolism in cancer
OpenAlex ID: W3188299482