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.
Highlights
Metabolic reprogramming is a hallmark of cancer
As T cells progress through thymic development, T-cell receptor (TCR) rearrangements are coordinated with NOTCH1 signaling and rapid cell proliferation in the thymus
In the context of acute myeloid leukemia (AML), we previously demonstrated that MYC binds at promoter sites of one-carbon folate
Summary
Metabolic reprogramming is a hallmark of cancer. As early as the 1920s, Warburg et al observed that tumor cells consume glucose at a high rate and do fermentation even in the presence of oxygen [1]. T-cell activation and development rely on other coordinated pathways, including one-carbon folate, serine biosynthesis, and mitochondrial proliferation [5, 6]. As a master regulator of cell proliferation, cell cycle progression, genetic instability, and metabolism [9], MYC commonly plays a role in cancer pathogenesis It stimulates expression of many nuclear encoded mitochondrial genes, regulates mitochondrial biogenesis [10], and is implicated in controlling the one-carbon folate pathway, especially in hypoxic conditions [11, 12]. Development of one-carbon folate pathway inhibitors has yielded highly active drugs, such as methotrexate (targeting repository https://www.ncbi.nlm.nih.gov/geo/ (GSE143176) and analyses are described in Supplementary Methods.
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