An MYC-Driven Vicious Circuit Is a Targetable Achilles' Heel in Lymphoma

Abstract

In this issue of Blood Cancer Discovery, Nakanishi et al. uncover a critical role for the elevated activity of the translation initiation factor eIF5A in the malignant growth of MYC-driven lymphoma. eIF5A is posttranslationally modified by hypusination through MYC oncoprotein-mediated hyperactivation of the polyamine-hypusine circuit, which may represent a promising therapeutic target because an enzyme of this circuit that is required for hypusinating eIF5A proved to be essential for lymphoma development. See related article by Nakanishi et al., p. 294 (4).

Figure 1.

Model: Proposed transcriptional and translational mechanisms involved in mediating MYC-driven lymphomagenesis in Eμ-Myc mice as the results of hyperactivation of the polyamine–hypusine circuit and eIF5A^Hyp-dependent translation of specific target mRNAs. Left, MYC overexpression in Eμ-Myc B cells transcriptionally upregulates genes encoding enzymes of the polyamine–hypusine circuit, in turn generating increased amounts of hypusinated eIF5A. Red arrows indicate the upregulation of gene expression. Hyp, hypusine; SAM, S-adenosylmethionine; dcSAM, decarboxy SAM; AMD1, adenosylmethionine decarboxylase-1; ODC1, ornithine decarboxylase-1; SRM, spermidine synthase; SMS, spermine synthase; DHPS, deoxyhypusine synthase; DOHH, deoxyhypusine hydroxylase; GC7, N1-guanyl-1, 7-diamine-heptane. GC7 is an inhibitor of DHPS. Right, Hypusinated eIF5A enhances translation of mRNA transcripts with roles in the cell cycle and known oncogenic effects in cancer. Red arrows indicate faster progression through the G₁–S transition and DNA replication. Nakanishi and colleagues propose that these mechanisms substantially contribute to MYC-driven lymphomagenesis observed in Eμ-Myc mice, in addition to other MYC-controlled (eIF5A^Hyp-independent) biological programs.