Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes

Aumann, Waitman K.; Heath, Jessica L.; Conway, Amanda E.; Sze, Sei-Gyung K.; Gupta, Veerain; Kazi, Rafi; Tope, Donald; Wechsler, Daniel S.; Lavau, Catherine

doi:10.1038/s41375-020-0998-3

Cited by 2 publications

(1 citation statement)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The ENL protein in the AF10 fusion complexes requires an intact YEATS domain that binds to acetylated histone H3 lysine 18/27 (H3K18/27ac) 31,32 and MOZ/MORF KATs 7 , and an intact AHD domain that binds to DOT1L and AF4 family proteins 8 . XPO1 is reportedly associated with the NES in CALM 33 and fuses with AF10 in human leukemia 41 . The current paradigm states that XPO1 serves as a recruiting factor that binds to the HOXA loci and recruits AF10 fusion complexes 33 .…”

Section: Discussionmentioning

confidence: 98%

MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

et al. 2023

View full text Add to dashboard Cite

Changes in the transcriptional machinery cause aberrant self-renewal of non-stem hematopoietic progenitors. AF10 fusions, such as CALM-AF10, are generated via chromosomal translocations, causing malignant leukemia. In this study, we demonstrate that AF10 fusion proteins cause aberrant self-renewal via ENL, which binds to MOZ/MORF lysine acetyltransferases (KATs). The interaction of ENL with MOZ, via its YEATS domain, is critical for CALM-AF10-mediated leukemic transformation. The MOZ/ENL complex recruits DOT1L/AF10 fusion complexes and maintains their chromatin retention via KAT activity. Therefore, inhibitors of MOZ/MORF KATs directly suppress the functions of AF10 fusion proteins, thereby exhibiting strong antitumor effects on AF10 translocation-induced leukemia. Combinatorial inhibition of MOZ/MORF and DOT1L cooperatively induces differentiation of CALM-AF10-leukemia cells. These results reveal roles for the MOZ/ENL complex as an essential recruiting factor of the AF10 fusion/DOT1L complex, providing a rationale for using MOZ/MORF KAT inhibitors in AF10 translocation-induced leukemia.

show abstract

Section: Discussionmentioning

confidence: 98%

MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

et al. 2023

View full text Add to dashboard Cite

show abstract

Exportin-1 functions as an adaptor for transcription factor-mediated docking of chromatin at the nuclear pore complex

Ge,

Brickner,

Zehr

et al. 2024

Preprint

View full text Add to dashboard Cite

Nuclear pore proteins (Nups) in yeast, flies and mammals physically interact with hundreds or thousands of chromosomal sites, which impacts transcriptional regulation. In budding yeast, transcription factors mediate interaction of Nups with enhancers of highly active genes. To define the molecular basis of this mechanism, we exploited a separation-of-function mutation in the Gcn4 transcription factor that blocks its interaction with the nuclear pore complex (NPC) without altering its DNA binding or activation domains. SILAC mass spectrometry revealed that this mutation reduces the interaction of Gcn4 with the highly conserved nuclear export factor Crm1/Xpo1. Crm1 both interacts with the same sites as Nups genome-wide and is required for Nup2 to interact with the yeast genome. In vivo, Crm1 undergoes extensive and stable interactions with the NPC. In vitro, Crm1 binds to Gcn4 and these proteins form a complex with the nuclear pore protein Nup2. Importantly, the interaction between Crm1 and Gcn4 does not require Ran-GTP, suggesting that it is not through the nuclear export sequence binding site. Finally, Crm1 stimulates DNA binding by Gcn4, supporting a model in which allosteric coupling between Crm1 binding and DNA binding permits docking of transcription factor-bound enhancers at the NPC.

show abstract

Fusion of the CRM1 nuclear export receptor to AF10 causes leukemia and transcriptional activation of HOXA genes

Cited by 2 publications

References 15 publications

MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

MOZ/ENL complex is a recruiting factor of leukemic AF10 fusion proteins

Exportin-1 functions as an adaptor for transcription factor-mediated docking of chromatin at the nuclear pore complex

Contact Info

Product

Resources

About