NUP214 in Leukemia: It's More than Transport

Abstract

NUP214 is a component of the nuclear pore complex (NPC) with a key role in protein and mRNA nuclear export. Chromosomal translocations involving the NUP214 locus are recurrent in acute leukemia and frequently fuse the C-terminal region of NUP214 with SET and DEK, two chromatin remodeling proteins with roles in transcription regulation. SET-NUP214 and DEK-NUP214 fusion proteins disrupt protein nuclear export by inhibition of the nuclear export receptor CRM1, which results in the aberrant accumulation of CRM1 protein cargoes in the nucleus. SET-NUP214 is primarily associated with acute lymphoblastic leukemia (ALL), whereas DEK-NUP214 exclusively results in acute myeloid leukemia (AML), indicating different leukemogenic driver mechanisms. Secondary mutations in leukemic blasts may contribute to the different leukemia outcomes. Additional layers of complexity arise from the respective functions of SET and DEK in transcription regulation and chromatin remodeling, which may drive malignant hematopoietic transformation more towards ALL or AML. Another, less frequent fusion protein involving the C terminus of NUP214 results in the sequestosome-1 (SQSTM1)-NUP214 chimera, which was detected in ALL. SQSTM1 is a ubiquitin-binding protein required for proper autophagy induction, linking the NUP214 fusion protein to yet another cellular mechanism. The scope of this review is to summarize the general features of NUP214-related leukemia and discuss how distinct chromosomal translocation partners can influence the cellular effects of NUP214 fusion proteins in leukemia.

Keywords: CRM1; DEK; HOX genes; NUP214; SET; chromatin remodeling; leukemia; nucleocytoplasmic transport; transcription.

Figure 1

Schematic representation of the human nuclear pore complex (NPC) and the localization of nucleoporins within the NPC 3D structure. The NUP214-NUP88 complex, which is localized in the cytoplasmic side of the NPC, is highlighted in blue.

Figure 2

Schematic representation of NUP214 and its binding partners in leukemogenic NUP214 fusion proteins. The numbers indicate the specific domains of each protein. Crossing lines (\\) represent the breakpoints in the respective fusion protein. NUP214: 1—β propeller, 2—Coiled coil, 3—FxFG domain; SET: 1—dimerization domain, 2—earmuff domain, 3—acidic domain; DEK: 1—SAF-box domain, 2—acidic domains (overlaps with the second DNA binding domain, represented by the arrow); SQSTM1: 1—PB1 domain, 2—Zinc Finger, 3—TB domain, 4—LIR domain, 5—UBA domain.

Figure 3

Putative models of gene regulation by SET-NUP214, DEK-NUP214, and SQSTM1-NUP214 fusion proteins. (A) Inhibition of CRM1-mediated nuclear export by sequestering nuclear export complexes into nuclear bodies formed by the fusion proteins. This may lead to nuclear accumulation of transcription factors that activate of HOX gene expression; (B) Spreading of histone hypoacetylation and transcriptional repression of genes involved in HOX activation. SET and DEK inhibit the transcriptional activity of the HATs p300/CBP and PCAF. Upon transcriptional stimuli, the interaction of SET and DEK with histone lysines is disrupted and HATs can co-activate transcription. In leukemia, SET-NUP214 preserves the dimerization domain of SET. SET-NUP214 may enhance the binding of endogenous SET to histones, in a mechanism similar to histone masking. DEK-NUP214 retains most of the histone binding domains of DEK and thus it may preserve histone binding capacity. In this model, DEK-NUP214 recruits additional, yet unknown, factors to chromatin. The NUP214_FG portion of the fusion proteins may contribute to aberrant histone hypoacetylation activity of SET and DEK due to their altered intracellular localization, which would result in the transcriptional repression of otherwise active genes.

Figure 4

Potential mechanisms for upregulation of HOX genes by SET-NUP214 and DEK-NUP214. (A) In normal cells, SET acts jointly with MLL to promote HOX gene expression. HOX genes are progressively silenced during cell differentiation. In leukemia cells, SET-NUP214 recruits endogenous SET and DOT1L to maintain high HOX expression levels. Additional factors might be necessary to sustain HOX expression. (B) DEK and the myeloid transcription factor C/EBPα cooperate to promote C/EBPα-mediated myeloid differentiation. FLT3 and FLT3-ITD can disrupt the interaction between DEK and C/EBPα, either by phosphorylation or inhibition of C/EBPα transcription. DEK-NUP214 may cooperate with wild-type FLT3 to inhibit C/EBPα activity by increasing its phosphorylation. This might be further potentiated by DEK-NUP214.