The interaction between NUP98 fusions and histone-modifying complexes promotes AML.

  • Major finding: The interaction between NUP98 fusions and histone-modifying complexes promotes AML.

  • Mechanism: NUP98 fusion proteins interact with MLL1 and NSL complexes at active Hox promoters in AML.

  • Impact: Disruption of the MLL1 complex may be a therapeutic strategy for patients with NUP98-fusion AML.

Nucleoporin 98 (NUP98) fusion proteins are typically comprised of the amino terminal of NUD98 and numerous partner proteins, such as Homeobox A9 (HOXA9), and have been shown to share common target genes and drive leukemogenesis. The amino terminal of NUP98, which is comprised of nontandem phenylalanine (F)–X–F–glycine (G) (FG) or G–leucine (L)–F–G (GLFG) repeats followed by the Gle2-binding sequence, mediates the localization of NUD98 to the nuclear pore complex and the inner nuclear envelope. Recently, the Drosophila homolog of NUP98 was shown to interact with the nonspecific lethal (NSL) and trithorax/mixed-lineage leukemia 1 (Trx/MLL) histone-modifying complexes to drive the expression of Hox genes, which are dysregulated in acute myeloid leukemia (AML). To identify the mechanisms underlying NUP98 fusion–mediated leukemogenesis and the upregulation of HOX genes in AML, Xu, Valerio, and colleagues examined the interactions between NUP98 fusion proteins with MLL1 and NSL in NUP98 fusion AML. NUP98 fusions localized to the nucleus and interacted with MLL1 and NSL complexes via FG/GLFG repeats in the amino terminal of NUP98 to colocalize at the Hoxa and Hoxb gene cluster loci and induce the expression of Hoxa and Hoxb gene clusters. Ablation of Mll1 decreased NUP98 fusion–driven AML leukemogenesis in vitro and in vivo, and Mll1-deleted NUD98 fusion–driven murine AML exhibited an MLL1-dependent transcriptomic signature resembling that of pediatric NUP98–nuclear receptor-binding SET domain protein 1 (NSD1) AML. Consistent with these findings, overexpression of the Hox genes Hoxa9 and Meis1 homeobox1 (Meis1), which were downregulated in Mll1-ablated NUP98-driven AML, rescued NUP98 fusion–driven AML from MLL dependence in vitro and in vivo. Together, these results elucidate the role of NUP98 fusions in MLL/NSL-mediated transcriptional activation of drivers of AML and provide a rationale for therapeutically targeting the MLL1 complex and perhaps the NSL complex in NUP98 fusion–driven AML.

Xu H, Valerio DG, Eisold ME, Sinha A, Koche RP, Hu W, et al. NUP98 fusion proteins interact with the NSL and MLL1 complexes to drive leukemogenesis. Cancer Cell 2016 Nov 23 [Epub ahead of print].

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.