c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation
Open accessAbstract
The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.
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?
IL-1 downregulates expression of Myc, a crucial upstream regulator of protein synthesis and cell cycle genes that leads to defective cell cycle entry if deleted in stem cells.
“Likewise, IL-1 downregulates expression of Myc, a crucial upstream regulator of protein synthesis and cell cycle genes that leads to defective cell cycle entry if deleted in stem cells (Laurenti et al., 2008; Scognamiglio et al., 2016; Wilson et al., 2004).”
From PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress (2021) · cites this paper as Wilson et al., 2004
The Abstract describes c-Myc as a regulator of target genes and cell division, and the Results report that its loss impairs proliferation of lineage-committed bone-marrow cells. But the section “Proliferation and survival of HSCs in vivo is c-Myc independent” says hematopoietic stem cells proliferate without c-Myc, contrary to the claimed defect in stem-cell cycle entry. The passages found do not establish that IL-1 downregulates Myc or that Myc regulates protein-synthesis genes. Page numbers were not provided for these indexed passages. (LLM, conf=0.89)
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
A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
Akashi, K., Traver, D., Miyamoto, T., & Weissman, I. L. (2000) · Nature · doi:10.1038/35004599 · Cited by 2,617 · see citing works
Cotsarelis, G., Sun, T.-T., & Lavker, R. M. (1990) · Cell · doi:10.1016/0092-8674(90)90696-c · Cited by 2,276 · see citing works
Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells.
Park, I.-K., Qian, D., Kiel, M., Becker, M. W., Pihalja, M., Weissman, I. L., Morrison, S. J., & Clarke, M. F. (2003) · Nature · doi:10.1038/nature01587 · Cited by 1,871 · see citing works
Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations
Weissman, I. L., Anderson, D. J., & Gage, F. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.387 · Cited by 948 · see citing works
Deregulated expression of c-Myc depletes epidermal stem cells
Waikel, R. L., Kawachi, Y., Waikel, P. A., Wang, X.-J., & Roop, D. R. (2001) · Nature Genetics · doi:10.1038/88889 · Cited by 318 · see citing works
Hematopoietic development: a balancing act
Cantor, A. B., & Orkin, S. H. (2001) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00226-4 · Cited by 191 · see citing works
Flagged first, then by citations
Research works printed but not linked: 6
- Christensen, J.L. and Weissman, I.L. 2001. Flk-2 is a marker in hematopoietic stem cell differentiation: A simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. 98: 14541-14546.
- Morrison, S.J., Wright, D.E., and Weissman, I.L. 1997. Cyclo- phosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl. Acad. Sci. 94: 1908-1913.
- Smith, L.G., Weissman, I.L., and Heimfeld, S. 1991. Clonal analysis of hematopoietic stem-cell differentiation in vivo. Proc. Natl. Acad. Sci. 88: 2788-2792.
- Song, X. and Xie, T. 2002. DE-cadherin-mediated cell adhesion is essential for maintaining somatic stem cells in the Dro- sophila ovary. Proc. Natl. Acad. Sci. 99: 14813-14818.
- Sperger, J.M., Chen, X., Draper, J.S., Antosiewicz, J.E., Chon, C.H., Jones, S.B., Brooks, J.D., Andrews, P.W., Brown, P.O., and Thomson, J.A. 2003. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tu- mors. Proc. Natl. Acad. Sci. 100: 13350-13355.
- Stappenbeck, T.S., Mills, J.C., and Gordon, J.I. 2003. Molecular features of adult mouse small intestinal epithelial progeni- tors. Proc. Natl. Acad. Sci. 100: 1004-1009.
Cited by
Sorted by citations
Kiel, M. J., Yilmaz, Ö. H., Iwashita, T., Yilmaz, O. H., Terhorst, C., & Morrison, S. J. (2005) · Cell · doi:10.1016/j.cell.2005.05.026 · Cited by 3,168 · see citing works
The bone marrow niche for haematopoietic stem cells
Morrison, S. J., & Scadden, D. T. (2014) · Nature · doi:10.1038/nature12984 · Cited by 2,451 · see citing works
Wilson, A., Laurenti, E., Oser, G., van der Wath, R. C., Blanco-Bose, W., Jaworski, M., Offner, S., Dunant, C. F., Eshkind, L., Bockamp, E., et al. (2008) · Cell · doi:10.1016/j.cell.2008.10.048 · Cited by 1,908 · see citing works
Self-citationIFNα activates dormant haematopoietic stem cells in vivo
Essers, M. A. G., Offner, S., Blanco-Bose, W. E., Waibler, Z., Kalinke, U., Duchosal, M. A., & Trumpp, A. (2009) · Nature · doi:10.1038/nature07815 · Cited by 1,368 · see citing works
Self-citationDang, C. V., O’Donnell, K. A., Zeller, K. I., Nguyen, T., Osthus, R. C., & Li, F. (2006) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2006.07.014 · Cited by 1,188 · see citing works
Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment
Naveiras, O., Nardi, V., Wenzel, P. L., Hauschka, P. V., Fahey, F., & Daley, G. Q. (2009) · Nature · doi:10.1038/nature08099 · Cited by 1,129 · see citing works
MYC as a regulator of ribosome biogenesis and protein synthesis
van Riggelen, J., Yetil, A., & Felsher, D. W. (2010) · Nature Reviews Cancer · doi:10.1038/nrc2819 · Cited by 956 · see citing works
Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation
Orford, K. W., & Scadden, D. T. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2269 · Cited by 851 · see citing works
PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention
Zhang, J., Grindley, J. C., Yin, T., Jayasinghe, S., He, X. C., Ross, J. T., Haug, J. S., Rupp, D., Porter-Westpfahl, K. S., Wiedemann, L. M., et al. (2006) · Nature · doi:10.1038/nature04747 · Cited by 817 · see citing works
A single-cell resolution map of mouse hematopoietic stem and progenitor cell differentiation
Nestorowa, S., Hamey, F. K., Pijuan Sala, B., Diamanti, E., Shepherd, M., Laurenti, E., Wilson, N. K., Kent, D. G., & Göttgens, B. (2016) · Blood · doi:10.1182/blood-2016-05-716480 · Cited by 768 · see citing works
Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition)
Cossarizza, A., Chang, H., Radbruch, A., Abrignani, S., Addo, R., Akdis, M., Andrä, I., Andreata, F., Annunziato, F., Arranz, E., et al. (2021) · European Journal of Immunology · doi:10.1002/eji.202170126 · Cited by 531 · see citing works
MYC: Connecting selective transcriptional control to global RNA production
Kress, T. R., Sabò, A., & Amati, B. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3984 · Cited by 521 · see citing works
Choi, J., Southworth, L. K., Sarin, K. Y., Venteicher, A. S., Ma, W., Chang, W., Cheung, P., Jun, S., Artandi, M. K., Shah, N., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.0040010 · Cited by 336 · see citing works
A Myc enhancer cluster regulates normal and leukaemic haematopoietic stem cell hierarchies
Bahr, C., von Paleske, L., Uslu, V. V., Remeseiro, S., Takayama, N., Ng, S. W., Murison, A., Langenfeld, K., Petretich, M., Scognamiglio, R., et al. (2018) · Nature · doi:10.1038/nature25193 · Cited by 328 · see citing works
Canonical Notch Signaling Is Dispensable for the Maintenance of Adult Hematopoietic Stem Cells
Maillard, I., Koch, U., Dumortier, A., Shestova, O., Xu, L., Sai, H., Pross, S. E., Aster, J. C., Bhandoola, A., Radtke, F., et al. (2008) · Cell Stem Cell · doi:10.1016/j.stem.2008.02.011 · Cited by 317 · see citing works
Chaperone-mediated autophagy sustains haematopoietic stem-cell function
Dong, S., Wang, Q., Kao, Y.-R., Diaz, A., Tasset, I., Kaushik, S., Thiruthuvanathan, V., Zintiridou, A., Nieves, E., Dzieciatkowska, M., et al. (2021) · Nature · doi:10.1038/s41586-020-03129-z · Cited by 275 · see citing works
DNA methylation disruption reshapes the hematopoietic differentiation landscape
Izzo, F., Lee, S. C., Poran, A., Chaligne, R., Gaiti, F., Gross, B., Murali, R. R., Deochand, S. D., Ang, C., Jones, P. W., et al. (2020) · Nature Genetics · doi:10.1038/s41588-020-0595-4 · Cited by 236 · see citing works
Sprüssel, A., Schulte, J. H., Weber, S., Necke, M., Händschke, K., Thor, T., Pajtler, K. W., Schramm, A., König, K., Diehl, L., et al. (2012) · Leukemia · doi:10.1038/leu.2012.157 · Cited by 203 · see citing works
MYC suppresses cancer metastasis by direct transcriptional silencing of αv and β3 integrin subunits
Liu, H., Radisky, D. C., Yang, D., Xu, R., Radisky, E. S., Bissell, M. J., & Bishop, J. M. (2012) · Nature Cell Biology · doi:10.1038/ncb2491 · Cited by 181 · see citing works
MYC in mammalian epidermis: how can an oncogene stimulate differentiation?
Watt, F. M., Frye, M., & Benitah, S. A. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2328 · Cited by 157 · see citing works
Pyruvate and metabolic flexibility: illuminating a path toward selective cancer therapies
Olson, K. A., Schell, J. C., & Rutter, J. (2016) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2016.01.002 · Cited by 154 · see citing works
Blanco‐Bose, W. E., Murphy, M. J., Ehninger, A., Offner, S., Dubey, C., Huang, W., Moore, D. D., & Trumpp, A. (2008) · Hepatology · doi:10.1002/hep.22475 · Cited by 138 · see citing works
Self-citationZanet, J., Pibre, S., Jacquet, C., Ramirez, A., de Alborán, I. M., & Gandarillas, A. (2005) · Journal of Cell Science · doi:10.1242/jcs.02298 · Cited by 123 · see citing works
Myc regulates keratinocyte adhesion and differentiation via complex formation with Miz1
Gebhardt, A., Frye, M., Herold, S., Benitah, S. A., Braun, K., Samans, B., Watt, F. M., Elsässer, H.-P., & Eilers, M. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200506057 · Cited by 118 · see citing works
c-Myc regulates cell size and ploidy but is not essential for postnatal proliferation in liver
Baena, E., Gandarillas, A., Vallespinós, M., Zanet, J., Bachs, O., Redondo, C., Fabregat, I., Martinez-A., C., & de Alborán, I. M. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0409260102 · Cited by 104 · see citing works
Araki, H., Yoshinaga, K., Boccuni, P., Zhao, Y., Hoffman, R., & Mahmud, N. (2007) · Blood · doi:10.1182/blood-2006-07-035287 · Cited by 98 · see citing works
PU.1 enforces quiescence and limits hematopoietic stem cell expansion during inflammatory stress
Chavez, J. S., Rabe, J. L., Loeffler, D., Higa, K. C., Hernandez, G., Mills, T. S., Ahmed, N., Gessner, R. L., Ke, Z., Idler, B. M., et al. (2021) · Journal of Experimental Medicine · doi:10.1084/jem.20201169 · Cited by 91 · see citing works
“Likewise, IL-1 downregulates expression of c-Myc, a crucial upstream regulator of protein synthesis and cell cycle genes that leads to defective cell cycle entry if deleted in stem cells (Laurenti et al., 2008; Scognamiglio et al., 2016; Wilson et al., 2004).”
BackgroundWalkley, C. R., & Orkin, S. H. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603389103 · Cited by 71 · see citing works
Hernandez, G., Mills, T. S., Rabe, J. L., Chavez, J. S., Kuldanek, S., Kirkpatrick, G., Noetzli, L., Jubair, W. K., Zanche, M., Myers, J. R., et al. (2020) · Haematologica · doi:10.3324/haematol.2018.197210 · Cited by 58 · see citing works
Jeong, M., Piao, Z.-H., Kim, M. S., Lee, S. H., Yun, S., Sun, H.-N., Yoon, S. R., Chung, J. W., Kim, T.-D., Jeon, J. H., et al. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0804221 · Cited by 58 · see citing works
Loss of Kat2a enhances transcriptional noise and depletes acute myeloid leukemia stem-like cells
Domingues, A. F., Kulkarni, R., Giotopoulos, G., Gupta, S., Vinnenberg, L., Arede, L., Foerner, E., Khalili, M., Adao, R. R., Johns, A., et al. (2020) · eLife · doi:10.7554/elife.51754 · Cited by 52 · see citing works
CIP2A increases self-renewal and is linked to Myc in neural progenitor cells
Kerosuo, L., Fox, H., Perälä, N., Ahlqvist, K., Suomalainen, A., Westermarck, J., Sariola, H., & Wartiovaara, K. (2010) · Differentiation · doi:10.1016/j.diff.2010.04.003 · Cited by 35 · see citing works
Strategies for elevating hematopoietic stem cells expansion and engraftment capacity
Derakhshani, M., Abbaszadeh, H., Movassaghpour, A. A., Mehdizadeh, A., Ebrahimi-Warkiani, M., & Yousefi, M. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116598 · Cited by 28 · see citing works
Janghorban, M., Langer, E. M., Wang, X., Zachman, D., Daniel, C. J., Hooper, J., Fleming, W. H., Agarwal, A., & Sears, R. C. (2017) · PLoS ONE · doi:10.1371/journal.pone.0188910 · Cited by 19 · see citing works
The bone marrow hematopoietic niche and its adaptation to infection
Gomes, A. C., Saraiva, M., & Gomes, M. S. (2021) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2020.05.014 · Cited by 18 · see citing works
- Authors
- Wilson, A., Murphy, M. J., Oskarsson, T., Kaloulis, K., Bettess, M. D., Oser, G. M., Pasche, A.-C., Knabenhans, C., MacDonald, H. R., & Trumpp, A.
- Affiliations
- ISREC Foundation (CH)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2004-11-15
- Volume
- 18
- Issue
- 22
- Pages
- 2747-2763
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC528895
- OpenAlex
- W2066277278
- Cited by
- 823
- References
- 6
- Citations by year
- 2026: 9 · 2025: 25 · 2024: 28 · 2023: 32 · 2022: 25 · 2021: 49 · 2020: 48 · 2019: 34 · 2018: 39 · 2017: 26 · 2016: 37 · 2015: 34 · 2014: 36 · 2013: 33 · 2012: 38
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- IRIS (submittedVersion)
- SERVAL (Université de Lausanne) (submittedVersion)
- Funders
- National Science Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- UBS Optimus Foundation
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- c-Myc, hematopoietic stem cells, stem cell self-renewal, stem cell differentiation, hematopoietic homeostasis, bone marrow microenvironment, N-cadherin, integrins, cell adhesion receptors, conditional knockout, cytopenia, stem cell niche
- MeSH terms
- Anemia, Animals, Bone Marrow, Cell Adhesion, Cell Differentiation, Cell Survival, Female, Hematopoiesis, Hematopoietic Stem Cells, Humans, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Cell Surface, RNA, Messenger, Cadherins, Up-Regulation, Integrins, Proto-Oncogene Proteins c-myc, Integrases, Reverse Transcriptase Polymerase Chain Reaction, Mice
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
