PU.1 induces apoptosis in myeloma cells through direct transactivation of TRAIL.
Open accessAbstract
We earlier reported that PU.1 was downregulated in myeloma cell lines and myeloma cells in a subset of myeloma patients, and that conditional PU.1 expression in PU.1-negative myeloma cell lines, U266 and KMS12PE, induced growth arrest and apoptosis. To elucidate the molecular mechanisms of the growth arrest and apoptosis, we performed DNA microarray analyses to compare the difference in gene expression before and after PU.1 induction in U266 cells. Among cell cycle-related genes, cyclin A2, cyclin B1, CDK2 and CDK4 were downregulated and p21 was upregulated, although among apoptosis-related genes, tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) was found highly upregulated. When TRAIL was knocked down by small interference RNAs, apoptosis of PU-1-expressing cells was inhibited, suggesting that TRAIL has a critical role in PU.1-induced apoptosis in both U266 and KMS12PE myeloma cells. In both U266 and KMS12PE cells expressing PU.1, PU.1 directly bound to a region 30 bp downstream of the transcription start site of the TRAIL gene. Upregulation of PU.1-induced transactivation of the TRAIL promoter in reporter assays, and disruption of the PU.1-binding site in the TRAIL promoter eliminated this transactivation. Therefore, we conclude that PU.1 is capable of inducing apoptosis in certain myeloma cells by direct transactivation of TRAIL.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In various cell types PU.1 induces expression of TRAIL and Ink4b, which respectively induce apoptosis and inhibit cell proliferation.
“In various cell types PU.1 has also been shown to induce expression of TRAIL and Ink4b, which respectively induce apoptosis and inhibit cell proliferation [28], [29].”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [28]
The Discussion (page unavailable) reports that PU.1 directly increases TRAIL expression and that TRAIL contributes to apoptosis in two myeloma cell lines. It explicitly says TRAIL induction in other hematopoietic lineages remains to be investigated, so this paper does not establish the broader claim about various cell types. Ink4b appears to be associated with the sentence’s other citation. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Antitumor Activity of Thalidomide in Refractory Multiple Myeloma
Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., Munshi, N., Anaissie, E., Wilson, C., Dhodapkar, M., et al. (1999) · New England Journal of Medicine · doi:10.1056/nejm199911183412102 · Cited by 2,575 · see citing works
Hideshima, T., Richardson, P. G. G., Chauhan, D., Palombella, V. J., Elliott, P. J., Adams, J., & Anderson, K. C. (2001) · PubMed · Cited by 1,518 · see citing works
Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities
McKercher, S. R., Torbett, B. E., Anderson, K. L., Henkel, G. W., Vestal, D. J., Baribault, H., Klemsz, M., Feeney, A. J., Wu, G. E., Paige, C. J., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00949.x · Cited by 1,130 · see citing works
Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma
Attal, M., Harousseau, J.-L., Facon, T., Guilhot, F., Doyen, C., Fuzibet, J.-G., Monconduit, M., Hulin, C., Caillot, D., Bouabdallah, R., et al. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa032290 · Cited by 984 · see citing works
The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene
Klemsz, M. J., McKercher, S. R., Celada, A., Van Beveren, C., & Maki, R. A. (1990) · Cell · doi:10.1016/0092-8674(90)90219-5 · Cited by 954 · see citing works
Single versus Double Autologous Stem-Cell Transplantation for Multiple Myeloma
(2004) · New England Journal of Medicine · doi:10.1056/nejm200406173502526 · Cited by 817 · see citing works
Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination
Klein, U., Casola, S. S., Cattoretti, G., Shen, Q. “., Lia, M., Mo, T., Ludwig, T. E., Rajewsky, K., & Dalla‐Favera, R. (2006) · Nature Immunology · doi:10.1038/ni1357 · Cited by 802 · see citing works
Loots, G. G., Locksley, R. M., Blankespoor, C. M., Wang, Z., Miller, W., Rubin, E. M., & Frazer, K. A. (2000) · Science · doi:10.1126/science.288.5463.136 · Cited by 783 · see citing works
IRF4 addiction in multiple myeloma
Shaffer, A. L., Emre, N. C. T., Lamy, L., Ngo, V. N., Wright, G., Xiao, W., Powell, J., Dave, S., Yu, X., Zhao, H., et al. (2008) · Nature · doi:10.1038/nature07064 · Cited by 730 · see citing works
Tumor-selective action of HDAC inhibitors involves TRAIL induction in acute myeloid leukemia cells
Nebbioso, A., Clarke, N., Voltz, E., Germain, E., Ambrosino, C., Bontempo, P., Álvarez, R., Schiavone, E. M., Ferrara, F., Bresciani, F., et al. (2004) · Nature Medicine · doi:10.1038/nm1161 · Cited by 613 · see citing works
Disruption of differentiation in human cancer: AML shows the way
Tenen, D. G. (2003) · Nature Reviews Cancer · doi:10.1038/nrc989 · Cited by 612 · see citing works
Self-citationInsinga, A., Monestiroli, S., Ronzoni, S., Gelmetti, V., Marchesi, F., Viale, A., Altucci, L., Nervi, C., Minucci, S., & Pelicci, P. G. (2004) · Nature Medicine · doi:10.1038/nm1160 · Cited by 512 · see citing works
Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1.
Rosenbauer, F., Wagner, K., Kutok, J. L., Iwasaki, H., Le Beau, M. M., Okuno, Y., Akashi, K., Fiering, S., & Tenen, D. G. (2004) · Nature Genetics · doi:10.1038/ng1361 · Cited by 506 · see citing works
Self-citationSpi-1 is a putative oncogene in virally induced murine erythroleukaemias
Moreau-Gachelin, F., Tavitian, A., & Tambourin, P. (1988) · Nature · doi:10.1038/331277a0 · Cited by 447 · see citing works
Mitsiades, C. S., Treon, S. P., Mitsiades, N., Shima, Y., Richardson, P. G. G., Schlossman, R. L., Hideshima, T., & Anderson, K. C. (2001) · Blood · doi:10.1182/blood.v98.3.795 · Cited by 391 · see citing works
Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma
Iida, S., Rao, P. H., Butler, M. P., Corradini, P., Boccadoro, M., Klein, B., CHAGANTI, R. S. K., & Dalla‐Favera, R. (1997) · Nature Genetics · doi:10.1038/ng1097-226 · Cited by 335 · see citing works
The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter
Pahl, H. L., Scheibe, R. J., Zhang, D. E., Chen, H. M., Galson, D. L., Maki, R. A., & Tenen, D. G. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)53496-7 · Cited by 301 · see citing works
Self-citationPU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis.
Huang, G., Zhang, P., Hirai, H., Elf, S., Yan, X., Chen, Z., Koschmieder, S., Okuno, Y., Dayaram, T., Growney, J. D., et al. (2008) · Nature Genetics · doi:10.1038/ng.2007.7 · Cited by 259 · see citing works
Self-citationRosenbauer, F., Owens, B. M., Yu, L., Tumang, J. R., Steidl, U., Kutok, J. L., Clayton, L. K., Wagner, K., Scheller, M., Iwasaki, H., et al. (2006) · Nature Genetics · doi:10.1038/ng1679 · Cited by 237 · see citing works
Self-citationPotential Autoregulation of Transcription Factor PU.1 by an Upstream Regulatory Element
Okuno, Y., Huang, G., Rosenbauer, F., Evans, E. K., Radomska, H. S., Iwasaki, H., Akashi, K., Moreau-Gachelin, F., Li, Y., Zhang, P., et al. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.7.2832-2845.2005 · Cited by 174 · see citing works
Self-citationGazitt, Y. (1999) · Leukemia · doi:10.1038/sj.leu.2401501 · Cited by 154 · see citing works
Mitsiades, N., Mitsiades, C. S., Poulaki, V., Anderson, K. C., & Treon, S. P. (2002) · Blood · doi:10.1182/blood.v99.6.2162 · Cited by 150 · see citing works
Mariani, S. M., Matiba, B., Armandola, E. A., & Krammer, P. H. (1997) · The Journal of Cell Biology · doi:10.1083/jcb.137.1.221 · Cited by 142 · see citing works
Coordinate Regulation of RAG1 and RAG2 by Cell Type-Specific DNA Elements 5' of RAG2
Yu, W., Misulovin, Z., Suh, H., Hardy, R. R., Janković, M., Yannoutsos, N., & Nussenzweig, M. C. (1999) · Science · doi:10.1126/science.285.5430.1080 · Cited by 139 · see citing works
Regulation of the PU.1 gene by distal elements
Li, Y., Okuno, Y., Zhang, P., Radomska, H. S., Chen, H.-M., Iwasaki, H., Akashi, K., Klemsz, M. J., McKercher, S. R., Maki, R. A., et al. (2001) · Blood · doi:10.1182/blood.v98.10.2958 · Cited by 110 · see citing works
Self-citationNovel therapeutic approaches for multiple myeloma
Hideshima, T., Richardson, P. G. G., & Anderson, K. C. (2003) · Immunological Reviews · doi:10.1034/j.1600-065x.2003.00053.x · Cited by 88 · see citing works
Differential regulation of the human and murine CD34 genes in hematopoietic stem cells
Okuno, Y., Iwasaki, H., Huettner, C. S., Radomska, H. S., Gonzalez, D. A., Tenen, D. G., & Akashi, K. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092027799 · Cited by 78 · see citing works
Self-citationIdentification of TRAIL as an Interferon Regulatory Factor 3 Transcriptional Target
Kirshner, J. R., Karpova, A. Y., Kops, M., & Howley, P. M. (2005) · Journal of Virology · doi:10.1128/jvi.79.14.9320-9324.2005 · Cited by 70 · see citing works
Activation and repression of the 2-5A synthetase and p21 gene promoters by IRF-1 and IRF-2
Coccia, E. M., Russo, N. D., Stellacci, E., Orsatti, R., Benedetti, E., Marziali, G., Hiscott, J. B., & Battistini, A. (1999) · Oncogene · doi:10.1038/sj.onc.1202536 · Cited by 68 · see citing works
IFI60/ISG60/IFIT4, a New Member of the Human IFI54/IFIT2 Family of Interferon-Stimulated Genes
de Veer, M. J., Sim, H., Whisstock, J. C., Devenish, R. J., & Ralph, S. J. (1998) · Genomics · doi:10.1006/geno.1998.5555 · Cited by 59 · see citing works
Transgenic targeting with regulatory elements of the human CD34 gene.
Radomska, H., Gonzalez, D. A., Okuno, Y., Iwasaki, H., Nagy, A., Akashi, K., Tenen, D., & Huettner, C. (2002) · Blood · doi:10.1182/blood-2002-02-0355 · Cited by 54 · see citing works
Self-citationTatetsu, H., Ueno, S., Hata, H., Yamada, Y., Takeya, M., Mitsuya, H., Tenen, D. G., & Okuno, Y. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4265 · Cited by 51 · see citing works
Self-citationDNA Methylation and Chromatin Structure Regulate PU.1 Expression
Amaravadi, L., & Klemsz, M. J. (1999) · DNA and Cell Biology · doi:10.1089/104454999314737 · Cited by 44 · see citing works
Distal elements are critical for human CD34 expression in vivo
Okuno, Y., Huettner, C. S., Radomska, H. S., Petkova, V., Iwasaki, H., Akashi, K., & Tenen, D. G. (2002) · Blood · doi:10.1182/blood-2002-03-0788 · Cited by 39 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
TRAIL receptor signaling and therapeutics
Abdulghani, J., & El‐Deiry, W. S. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728222.2010.519701 · Cited by 154 · see citing works
NF-κB/STAT5/miR-155 network targets PU.1 in FLT3-ITD-driven acute myeloid leukemia
Gerloff, D., Grundler, R., Wurm, A. A., Bräuer-Hartmann, D., Katzerke, C., Hartmann, J.-U., Madan, V, Müller-Tidow, C., Duyster, J., Tenen, D. G., et al. (2015) · Leukemia · doi:10.1038/leu.2014.231 · Cited by 135 · see citing works
Self-citationPU.1 is a potent tumor suppressor in classical Hodgkin lymphoma cells
Yuki, H., Ueno, S., Tatetsu, H., Niiro, H., Iino, T., Endo, S., Kawano, Y., Komohara, Y., Takeya, M., Hata, H., et al. (2012) · Blood · doi:10.1182/blood-2012-05-431429 · Cited by 47 · see citing works
Self-citationThe anti-apoptotic gene BCL2A1 is a novel transcriptional target of PU.1
Jenal, M., Batliner, J., Reddy, V. A., Haferlach, T., Tobler, A., Fey, M. F., Torbett, B. E., & Tschan, M. P. (2010) · Leukemia · doi:10.1038/leu.2010.26 · Cited by 40 · see citing works
Comprehensive Analysis of Immune Implications and Prognostic Value of SPI1 in Gastric Cancer
Huang, J., Chen, W., Jie, Z., & Jiang, M. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.820568 · Cited by 38 · see citing works
Siwaponanan, P., Siegers, J. Y., Ghazali, R., Ng, T., McColl, B., Ng, G. Z., SUTTON, P. R. N., Wang, N., Ooi, I., Thiengtavor, C., et al. (2017) · Blood · doi:10.1182/blood-2016-07-730135 · Cited by 36 · see citing works
PU.1 acts as tumor suppressor for myeloma cells through direct transcriptional repression of IRF4
Ueno, N., Nishimura, N., Ueno, S., Endo, S., Tatetsu, H., Hirata, S., Hata, H., Matsuoka, M., Mitsuya, H., & Okuno, Y. (2017) · Oncogene · doi:10.1038/onc.2017.79 · Cited by 34 · see citing works
Self-citationHaimovici, A., Humbert, M., Federzoni, E. A., Shan, D., Brunner, T., Frese, S., Kaufmann, T., Torbett, B. E., & Tschan, M. P. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.40 · Cited by 23 · see citing works
Endo, S., Amano, M., Nishimura, N., Ueno, N., Ueno, S., Yuki, H., Fujiwara, S., Wada, N. A., Hirata, S., Hata, H., et al. (2015) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2015.11.116 · Cited by 14 · see citing works
Self-citationPU.1 is a major transcriptional activator of the tumour suppressor geneLIMD1
Foxler, D. E., James, V. H., Shelton, S. J., Vallim, T. Q. D. A., Shaw, P. E., & Sharp, T. V. (2011) · FEBS Letters · doi:10.1016/j.febslet.2011.03.013 · Cited by 13 · see citing works
Goto, H., Kariya, R., Kudo, E., Okuno, Y., Ueda, K., Katano, H., & Okada, S. (2017) · Oncogene · doi:10.1038/onc.2017.138 · Cited by 10 · see citing works
Self-citationThe Transcription Factor PU.1 Regulates γδ T Cell Homeostasis
Jabeen, R., Chang, H.-C., Goswami, R., Nutt, S. L., & Kaplan, M. H. (2011) · PLOS ONE · doi:10.1371/journal.pone.0022189 · Cited by 10 · see citing works
Autophagy in RAW264.7 Cells Treated with Surface‐Functionalized Graphene Oxides
Park, C. S., Choi, K. S., Park, I. W., Jung, J., Choi, J. C., Kim, J. Y., Choi, B. W., Kim, Y. G., Shin, J. W., & Kim, S. Y. (2015) · Journal of Nanomaterials · doi:10.1155/2015/704789 · Cited by 9 · see citing works
PU.1 is a tumor suppressor for B cell malignancies
Okuno, Y., & Yuki, H. (2012) · Oncotarget · doi:10.18632/oncotarget.800 · Cited by 8 · see citing works
Self-citationPharmacological Targeting of IRF4 As a Therapeutic Strategy for Multiple Myeloma
Agius, M. P., Song, C., Liu, Q., Iemura, T., Hevenor, L., Payne, N. C., Sklavenitis‐Pistofidis, R., Pantano, L., Zhao, H., Seo, H., et al. (2024) · Nature Chemical Biology · doi:10.1038/s41589-026-02228-8 · Cited by 5 · see citing works
Hu, X., Cai, J., Zhu, J., Lang, W., Zhong, J., Zhong, H., & Chen, F. (2019) · Cellular Signalling · doi:10.1016/j.cellsig.2019.109409 · Cited by 4 · see citing works
Decreased PU.1 expression in mature B cells induces lymphomagenesis
Endo, S., Nishimura, N., Toyoda, K., Komohara, Y., Carreras, J., Yuki, H., Shichijo, T., Ueno, S., Ueno, N., Hirata, S., et al. (2024) · Cancer Science · doi:10.1111/cas.16344 · Cited by 3 · see citing works
Self-citationA xenograft model reveals that PU.1 functions as a tumor suppressor for multiple myeloma in vivo
Nishimura, N., Endo, S., Ueno, S., Ueno, N., Tatetsu, H., Hirata, S., Hata, H., Komohara, Y., Takeya, M., Mitsuya, H., et al. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.03.124 · Cited by 3 · see citing works
Self-citationPolymorphism Analysis of TRAIL Gene and Correlation TRAIL Expression in Prostate Cancer
Mi, Y., Zhu, L., & Feng, N. (2011) · InTech eBooks · doi:10.5772/26302 · Cited by 1 · see citing works
Chera, J. S., Kumar, S., Vats, A., Kushwaha, P., Behera, M., & De, S. (2021) · Veterinary Immunology and Immunopathology · doi:10.1016/j.vetimm.2021.110349 · Cited by 1 · see citing works
- Authors
- Ueno, S., Tatetsu, H., Hata, H., Iino, T., Niiro, H., Akashi, K., Tenen, D. G., Mitsuya, H., & Okuno, Y.
- Affiliations
- Kumamoto University (JP)
- Kyushu University (JP)
- Harvard University (US)
- Corresponding author
- Okuno, Y
- Venue
- Oncogene
- Published
- 2009-09-14
- Volume
- 28
- Issue
- 46
- Pages
- 4116-4125
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC2917647
- OpenAlex
- W2002225588
- Cited by
- 20
- References
- 34
- Citations by year
- 2024: 2 · 2022: 1 · 2021: 1 · 2019: 1 · 2017: 5 · 2015: 2 · 2014: 1 · 2012: 2
- FWCI
- 1.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- National University of Singapore (submittedVersion)
- Funders
- International Myeloma Foundation
- National Cancer Institute (R01CA041456)
- Topics
- Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- PU.1, TRAIL, multiple myeloma, apoptosis, transcriptional activation, transcription factor binding sites, U266 cells, gene expression profiling, p21
- MeSH terms
- Interferon Regulatory Factor-4, Proto-Oncogene Protein Spi-1, Cell Cycle, Humans, Interferons, Multiple Myeloma, Promoter Regions, Genetic, Protein Binding, Proto-Oncogene Proteins, Transcriptional Activation, Trans-Activators, Gene Expression Regulation, Neoplastic, Apoptosis, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Interferon Regulatory Factors, Interferon Regulatory Factor-7, TNF-Related Apoptosis-Inducing Ligand
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
