Therapy-resistant lymphomas may want nucleotides, but they just need to grow
Carlos Carmona-Fontaine
Carlos Carmona-Fontaine
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Therapy-resistant lymphomas may want nucleotides, but they just need to grow

Abstract

Malignant cells must rapidly synthesize nucleotides to grow and proliferate. Antimetabolite chemotherapies throw a wrench in this process by administering decoy molecules resembling nucleotide precursors that cells cannot use, such as 6-mercaptopurine (6MP) and methotrexate. While this approach remains an essential tool in the treatment of lymphoblastic leukemias and B cell non-Hodgkin lymphomas, approximately 1 in 3 patients will eventually develop therapy-resistant malignancies. In this issue of the JCI, Yang et al. investigated the metabolic adaptations that enable therapy-resistant tumors to grow in the presence of these drugs. Using their previously described mouse model of MYC-driven large B cell lymphoma, they identified that increased expression of the vesicular oligopeptide and histidine transporter SLC15A3 drives dipeptide accumulation in therapy-resistant cells. In lieu of finding other ways to make more nucleotides, these adaptations force cell growth by boosting mTOR signaling. This cunning adaptation, however, is also a vulnerability that can be targeted clinically.

Authors

Carlos Carmona-Fontaine

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Figure 1

Antimetabolite-resistant lymphomas circumvent the need for nucleotides by activating mTOR.

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Antimetabolite-resistant lymphomas circumvent the need for nucleotides b...
(A) Antimetabolite therapies like methotrexate and 6MP inhibit cell proliferation by reducing nucleotide biosynthesis, but many malignant lymphomas become resistant to these therapies. Yang et al. (1) used a Prps2–/– model of MYC-driven large B cell lymphoma to model resistance to nucleotide deficiency. They found that therapy-resistant lymphomas did not develop an ability to fix nucleotide scarcity. Instead, they overrode the growth inhibition by antimetabolite therapies through mTOR activation, forcing cells to proliferate. mTORC1, mTOR complex 1. (B) Mechanistically, they showed that increased expression of SLC15A3 led to accumulation of dipeptides, including glycyl-leucine, in therapy-resistant lymphomas, driving mTORC1 activation. SLC15A3 may directly or indirectly activate this complex, and Yang et al.’s metabolomic analyses suggested that vitamin D3 may negatively regulate Slc15a3 expression. Potential targets for therapeutic interventions are shown in red.