Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Mendes, Adélia; Jühlen, Ramona; Bousbata, Sabrina; Fahrenkrog, Birthe

doi:10.3390/cells9071666

Cited by 9 publications

(7 citation statements)

References 87 publications

(144 reference statements)

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“…Our results demonstrate that HOXA9 is overexpressed in aged SkMSCs compared with control samples and that miR-365a-3p reverses the suppressive effect of HOXA9 on SkMSC proliferation and differentiation. In accordance with these observations, some studies reported that HOXA9 is the direct target of miR-365a-3p [ 41 – 43 ]. Furthermore, circRNA FUT10 downregulation suppressed SkMSC proliferation and viability.…”

Section: Discussionsupporting

confidence: 65%

CircRNA FUT10 regulates the regenerative potential of aged skeletal muscle stem cells by targeting HOXA9

Zhu

Lian

Chen

et al. 2021

Aging

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Skeletal muscle is capable of repairing itself after injury to maintain the stability of its own tissue, but this ability declines with aging. Circular RNAs (circRNAs) are involved in cell aging. However, there is little research into their role and underlying mechanisms, especially in skeletal muscle stem cells (SkMSCs). In this study, we assessed circRNA FUT10 expression in aged and adult SkMSCs. We observed that circRNA FUT10 was upregulated in aged SkMSCs compared with that in adult SkMSCs. Furthermore, we identified putative miR-365-3p binding sites on circRNA FUT10, suggesting that this circRNA sponges miR-365a-3p. We also found that HOXA9 is a downstream target of miR-365a-3p and confirmed that miR-365a-3p can bind to circRNA FUT10 and the 3′-untranslated region of HOXA9 mRNA. This finding indicated that miR-365a-3p might serve as a “bridge” between circRNA FUT10 and HOXA9. Finally, we found that the circRNA FUT10/miR365a-3p/HOXA9 axis is involved in SkMSC aging. Collectively, our results show that the circRNA FUT10/miR365a-3p/HOXA9 axis is a promising therapeutic target and are expected to facilitate the development of therapeutic strategies to improve the prognosis of degenerative muscle disease.

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Section: Discussionsupporting

confidence: 65%

CircRNA FUT10 regulates the regenerative potential of aged skeletal muscle stem cells by targeting HOXA9

Zhu

Lian

Chen

et al. 2021

Aging

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“…MLL1 was shown to contribute to the oncogenic properties NA9 by recruiting NA9 to the HOXA/B locus via an interaction with the FG repeats of the NUP98 portion, thereby inducing HOXA/B gene expression [32,33]. Interestingly, a recent BioID screen conducted in the colon cancer cell line HCT-116, identified XPO1, RAE1, HDAC1 and MLL1 as proximal interactors of a NA9-BirA bait [34].…”

Section: Plos Geneticsmentioning

confidence: 99%

A genetic screen in Drosophila uncovers the multifaceted properties of the NUP98-HOXA9 oncogene

et al. 2021

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Acute myeloid leukemia (AML) underlies the uncontrolled accumulation of immature myeloid blasts. Several cytogenetic abnormalities have been associated with AML. Among these is the NUP98-HOXA9 (NA9) translocation that fuses the Phe-Gly repeats of nucleoporin NUP98 to the homeodomain of the transcription factor HOXA9. The mechanisms enabling NA9-induced leukemia are poorly understood. Here, we conducted a genetic screen in Drosophila for modifiers of NA9. The screen uncovered 29 complementation groups, including genes with mammalian homologs known to impinge on NA9 activity. Markedly, the modifiers encompassed a diversity of functional categories, suggesting that NA9 perturbs multiple intracellular events. Unexpectedly, we discovered that NA9 promotes cell fate transdetermination and that this phenomenon is greatly influenced by NA9 modifiers involved in epigenetic regulation. Together, our work reveals a network of genes functionally connected to NA9 that not only provides insights into its mechanism of action, but also represents potential therapeutic targets.

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“…Most of the attention on Nup98 translocations in cancer has focused on overexpressing Nup98 fusion partners. However when overexpressed, Nup98 has been shown to behave as a dominant negative and disrupt the nuclear envelope and nuclear transport (Fahrenkrog et al, 2016;Mendes et al, 2020), possibly by forming phase-separated aggregates outside of the nuclear pore (Ahn et al, 2021;Schmidt and Gorlich, 2015). We noted that Nup98 overexpression in the posterior wing reduced tissue size, and in severe cases disrupted pattering (Fig.…”

Section: Overexpression Of Nup98 Leads To Defects In Proteins Synthesis and Jnk Activationmentioning

confidence: 55%

Mis-regulation of the Nucleoporins 98 and 96 lead to defects in protein synthesis that promote hallmarks of tumorigenesis

Pulianmackal

Kanakousaki

Flegel

et al. 2021

Preprint

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The Nucleoporin 98KD (Nup98) is one of the most promiscuous translocation partners in hematological malignancies, contributing to at least 31 different truncation—fusion proteins. To date, nearly all disease models of Nup98 translocations involve ectopic expression of transgenes recapitulating the fusion protein under study, leaving the endogenous Nup98 loci unperturbed. Overlooked in these approaches is that translocation leads to the loss of one copy of normal Nup98 in addition to the loss of Nup96, a second Nucleoporin encoded within the same mRNA and reading frame as Nup98. Nup98 and 96 are also mutated in a number of other cancer types and are located near a tumor suppressor region known to be epigenetically silenced, suggesting that their disruption is not limited to blood cancers. We found that reducing Nup98—96 function via an RNAi approach in Drosophila melanogaster (where the Nup98—96 shared mRNA and reading frame gene structure is conserved) deregulates the cell cycle. We find evidence of overproliferation in Nup98—96 deficient tissues, counteracted by elevated apoptosis and aberrant Wingless and JNK signaling associated with chronic wound healing. When the knockdown of Nup98—96 is combined with inhibition of apoptosis, we see synergism leading to dramatic tissue overgrowth, consistent with a tumor suppressor function for endogenous Nup98 and 96. To understand how growth and proliferation become misregulated when Nup98—96 levels are reduced, we performed RNAseq and uncovered a gene expression signature consistent with defects in ribosome biogenesis. We found that reducing Nup 98 and 96 function limits nuclear export of the ribosome component RpL10A, leading to defects in protein synthesis. Defects in protein synthesis are sufficient to trigger JNK signaling that contributes to compensatory proliferation and hallmarks of tumorigenesis when apoptosis is inhibited. Based upon our data, we suggest that the partial loss of Nup98 and Nup96 function in translocations could de-regulate protein synthesis leading to stress signaling that cooperates with other mutations in cancer to promote tumorigenesis.

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Disclosing the Interactome of Leukemogenic NUP98-HOXA9 and SET-NUP214 Fusion Proteins Using a Proteomic Approach

Cited by 9 publications

References 87 publications

CircRNA FUT10 regulates the regenerative potential of aged skeletal muscle stem cells by targeting HOXA9

CircRNA FUT10 regulates the regenerative potential of aged skeletal muscle stem cells by targeting HOXA9

A genetic screen in Drosophila uncovers the multifaceted properties of the NUP98-HOXA9 oncogene

Mis-regulation of the Nucleoporins 98 and 96 lead to defects in protein synthesis that promote hallmarks of tumorigenesis

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