A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias

Conway, Amanda E.; Haldeman, Jonathan M.; Wechsler, Daniel S.; Lavau, Catherine

doi:10.1038/leu.2014.221

Cited by 31 publications

(22 citation statements)

References 44 publications

(66 reference statements)

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“…Notably, a recent report ( Conway et al, 2014 ) also demonstrated that Crm1 binds to the HoxA9 and HoxA10 gene regions, both in human leukemia cell line and immortalized mouse embryonic fibroblast cell line. Conway et al (2014) further showed that Crm1 recruits CALM-AF10 fusion through its interaction with the nuclear export signal on CALM to activate Hox gene expression. Thus, the association of Crm1 with Hox loci could be a common molecular basis for aberrant Hox gene dysregulation mediated by numerous leukemic fusions.…”

Section: Discussionmentioning

confidence: 93%

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

Oka

Mura

Yamada

et al. 2016

eLife

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The nucleoporin Nup98 is frequently rearranged to form leukemogenic Nup98-fusion proteins with various partners. However, their function remains largely elusive. Here, we show that Nup98-HoxA9, a fusion between Nup98 and the homeobox transcription factor HoxA9, forms nuclear aggregates that frequently associate with facultative heterochromatin. We demonstrate that stable expression of Nup98-HoxA9 in mouse embryonic stem cells selectively induces the expression of Hox cluster genes. Genome-wide binding site analysis revealed that Nup98-HoxA9 is preferentially targeted and accumulated at Hox cluster regions where the export factor Crm1 is originally prebound. In addition, leptomycin B, an inhibitor of Crm1, disassembled nuclear Nup98-HoxA9 dots, resulting in the loss of chromatin binding of Nup98-HoxA9 and Nup98-HoxA9-mediated activation of Hox genes. Collectively, our results indicate that highly selective targeting of Nup98-fusion proteins to Hox cluster regions via prebound Crm1 induces the formation of higher order chromatin structures that causes aberrant Hox gene regulation.DOI: http://dx.doi.org/10.7554/eLife.09540.001

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Section: Discussionmentioning

confidence: 93%

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

Oka

Mura

Yamada

et al. 2016

eLife

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“…As a result, a subset of genes might be affected with respect to their expression levels. Interestingly, the leukemogenic CALM-AF10 fusion protein is recruited to chromatin-bound CRM1, suggesting similar mechanisms that might lead to disease (58).…”

Section: Discussionmentioning

confidence: 99%

The Oncogenic Fusion Proteins SET-Nup214 and Sequestosome-1 (SQSTM1)-Nup214 Form Dynamic Nuclear Bodies and Differentially Affect Nuclear Protein and Poly(A)+ RNA Export

Port

Mendes

Valkova

et al. 2016

Journal of Biological Chemistry

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Genetic rearrangements are a hallmark of several forms of leukemia and can lead to oncogenic fusion proteins. One example of an affected chromosomal region is the gene coding for Nup214, a nucleoporin that localizes to the cytoplasmic side of the nuclear pore complex (NPC). We investigated two such fusion proteins, SET-Nup214 and SQSTM1 (sequestosome)-Nup214, both containing C-terminal portions of Nup214. SET-Nup214 nuclear bodies containing the nuclear export receptor CRM1 were observed in the leukemia cell lines LOUCY and MEGAL. Overexpression of SET-Nup214 in HeLa cells leads to the formation of similar nuclear bodies that recruit CRM1, export cargo proteins, and certain nucleoporins and concomitantly affect nuclear protein and poly(A) RNA export. SQSTM1-Nup214, although mostly cytoplasmic, also forms nuclear bodies and inhibits nuclear protein but not poly(A) RNA export. The interaction of the fusion proteins with CRM1 is RanGTP-dependent, as shown in co-immunoprecipitation experiments and binding assays. Further analysis revealed that the Nup214 parts mediate the inhibition of nuclear export, whereas the SET or SQSTM1 part determines the localization of the fusion protein and therefore the extent of the effect. SET-Nup214 nuclear bodies are highly mobile structures, which are in equilibrium with the nucleoplasm in interphase and disassemble during mitosis or upon treatment of cells with the CRM1-inhibitor leptomycin B. Strikingly, we found that nucleoporins can be released from nuclear bodies and reintegrated into existing NPC. Our results point to nuclear bodies as a means of preventing the formation of potentially insoluble and harmful protein aggregates that also may serve as storage compartments for nuclear transport factors.

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“…This review will focus on its role in cancer. 6 , 41 , 42 CRM1 is overexpressed in a large variety of tumors including lung cancer, 43 osteosarcoma, 44 glioma, 45 pancreatic cancer, 46 ovarian cancer, 47 , 48 cervical carcinoma, 49 renal cell carcinoma, 50 esophageal carcinoma, 51 gastric carcinoma, 52 hepatocellular carcinoma, 53 acute myeloid/lymphoid leukemia, 54 , 55 chronic myeloid/lymphoid leukemia, 56 mantle cell lymphoma, 57 , 58 plasma cell leukemia 59 and multiple myeloma. 59 , 60 In addition, CRM1 upregulation is associated with drug resistance and stands out as a poor prognosis factor in many malignancies.…”

Section: Nuclear Export Factor Crm1mentioning

confidence: 99%

Inhibiting cancer cell hallmark features through nuclear export inhibition

Sun

Chen

Zhou

et al. 2016

Sig Transduct Target Ther

120

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Treating cancer through inhibition of nuclear export is one of the best examples of basic research translation into clinical application. Nuclear export factor chromosomal region maintenance 1 (CRM1; Xpo1 and exportin-1) controls cellular localization and function of numerous proteins that are critical for the development of many cancer hallmarks. The diverse actions of CRM1 are likely to explain the broad ranging anti-cancer potency of CRM1 inhibitors observed in pre-clinical studies and/or clinical trials (phase I–III) on both advanced-stage solid and hematological tumors. In this review, we compare and contrast the mechanisms of action of different CRM1 inhibitors, and discuss the potential benefit of unexplored non-covalent CRM1 inhibitors. This emerging field has uncovered that nuclear export inhibition is well poised as an attractive target towards low-toxicity broad-spectrum potent anti-cancer therapy.

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A critical role for CRM1 in regulating HOXA gene transcription in CALM-AF10 leukemias

Cited by 31 publications

References 44 publications

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

Chromatin-prebound Crm1 recruits Nup98-HoxA9 fusion to induce aberrant expression of Hox cluster genes

The Oncogenic Fusion Proteins SET-Nup214 and Sequestosome-1 (SQSTM1)-Nup214 Form Dynamic Nuclear Bodies and Differentially Affect Nuclear Protein and Poly(A)+ RNA Export

Inhibiting cancer cell hallmark features through nuclear export inhibition

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