Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPα ratio and granulocyte colony-stimulating factor
Abstract
Hematopoietic transcription factors are essential for specifying cell fates; however, the function of cytokines in such developmental decisions is unresolved. We demonstrate here that haploinsufficiency for the gene encoding the transcription factor PU.1 partially suppresses the neutropenia of mice deficient in granulocyte colony-stimulating factor. This suppression was due to an increase in granulocytic progenitors and a diminution of monocytic progenitors. With (PU.1+/-) ES cells as well as (PU.1-/-) hematopoietic progenitors, we show that higher expression of PU.1 is needed for macrophage than for neutrophil development. In a (PU.1-/-) progenitor cell line, in which graded activity of PU.1 regulates neutrophil versus macrophage development, granulocyte colony-stimulating factor signaling supported the neutrophil cell fate by increasing expression of the neutrophil transcription factor C/EBPalpha in relation to expression of PU.1. Collectively, these results indicate that cytokines can promote cell fate decisions by altering the relative concentrations of lineage-determining transcriptional regulators.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Lower PU.1 protein abundance results in enhanced granulocytic lineage differentiation.
“which is consistent with lower PU.1 protein abundance resulting in enhanced granulocytic lineage differentiation (33).”
From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [33]
Altered ratios between TFs can be sufficient to establish specific gene expression programs.
“Indeed, altered ratios between TFs can be sufficient to establish specific gene expression programs.9,10”
From Design principles of cell-state-specific enhancers in hematopoiesis (2025) · cites this paper as [9]
Cites
Yoshida, H., Hayashi, S.-I., Kunisada, T., Ogawa, M., Nishikawa, S., Okamura, H., Sudo, T., Shultz, L. D., & Nishikawa, S.-I. (1990) · Nature · doi:10.1038/345442a0 · Cited by 1,789 · see citing works
Pevny, L., Simon, M. C., Robertson, E., Klein, W. H., Tsai, S.-F., D'Agati, V., Orkin, S. H., & Costantini, F. (1991) · Nature · doi:10.1038/349257a0 · Cited by 1,308 · see citing works
Self-citationPU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors
Nerlov, C., & Graf, T. (1998) · Genes & Development · doi:10.1101/gad.12.15.2403 · Cited by 449 · see citing works
PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding
Zhang, P., Zhang, X., Iwama, A., Yu, C., Smith, K. A., Mueller, B. U., Narravula, S., Torbett, B. E., Orkin, S. H., & Tenen, D. G. (2000) · Blood · doi:10.1182/blood.v96.8.2641 · Cited by 368 · see citing works
Specificity within the ets Family of Transcription Factors
(1998) · Advances in Cancer Research · doi:10.1016/s0065-230x(08)60738-1 · Cited by 344 · 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
DeKoter, R. P., Walsh, J. C., & Singh, H. (1998) · The EMBO Journal · doi:10.1093/emboj/17.15.4456 · Cited by 296 · see citing works
Self-citationWalsh, J. C., DeKoter, R. P., Lee, H.-J., Smith, E. D., Lancki, D. W., Gurish, M. F., Friend, D. S., Stevens, R. L., Anastasi, J., & Singh, H. (2002) · Immunity · doi:10.1016/s1074-7613(02)00452-1 · Cited by 262 · see citing works
Self-citationHematopoietic 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
Olson, M. C., Scott, E. W., Hack, A. A., Su, G. H., Tenen, D. G., Singh, H., & Simon, M. C. (1995) · Immunity · doi:10.1016/1074-7613(95)90060-8 · Cited by 191 · see citing works
Self-citationReddy, V. A., Iwama, A., Iotzova, G., Schulz, M., Elsasser, A., Vangala, R. K., Tenen, D. G., Hiddemann, W., & Behre, G. (2002) · Blood · doi:10.1182/blood.v100.2.483 · Cited by 152 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Neutrophil recruitment and function in health and inflammation
Kolaczkowska, E., & Kubes, P. (2013) · Nature Reviews Immunology · doi:10.1038/nri3399 · Cited by 5,472 · see citing works
Joshi, N. S., Cui, W., Chandele, A., Lee, H. K., Urso, D. R., Hagman, J., Gapin, L., & Kaech, S. M. (2007) · Immunity · doi:10.1016/j.immuni.2007.07.010 · Cited by 1,861 · see citing works
Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors
Paul, F., Arkin, Y., Giladi, A., Jaitin, D. A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.013 · Cited by 1,082 · see citing works
Multilineage Transcriptional Priming and Determination of Alternate Hematopoietic Cell Fates
Laslo, P., Spooner, C. J., Warmflash, A., Lancki, D. W., Lee, H.-J., Sciammas, R., Gantner, B. N., Dinner, A. R., & Singh, H. (2006) · Cell · doi:10.1016/j.cell.2006.06.052 · Cited by 632 · see citing works
Self-citationTranscription factors in myeloid development: balancing differentiation with transformation
Rosenbauer, F., & Tenen, D. G. (2007) · Nature Reviews Immunology · doi:10.1038/nri2024 · Cited by 606 · 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
Single-cell analysis of mixed-lineage states leading to a binary cell fate choice
Olsson, A., Venkatasubramanian, M., Chaudhri, V. K., Aronow, B. J., Salomonis, N., Singh, H., & Grimes, H. L. (2016) · Nature · doi:10.1038/nature19348 · Cited by 476 · see citing works
Self-citationTranscriptional control of granulocyte and monocyte development
Friedman, A. D. (2007) · Oncogene · doi:10.1038/sj.onc.1210764 · Cited by 427 · see citing works
Myeloid Lineage Commitment from the Hematopoietic Stem Cell
Iwasaki, H., & Akashi, K. (2007) · Immunity · doi:10.1016/j.immuni.2007.06.004 · Cited by 394 · see citing works
Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors
Nutt, S. L., Metcalf, D., D'Amico, A., Polli, M., & Wu, L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20041535 · Cited by 325 · see citing works
PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis
Dakic, A., Metcalf, D., Di Rago, L., Mifsud, S., Wu, L., & Nutt, S. L. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050075 · Cited by 297 · see citing works
The transcriptional program of terminal granulocytic differentiation
Theilgaard-Mönch, K., Jacobsen, L. C., Borup, R., Rasmussen, T., Bjerregaard, M. D., Nielsen, F. C., Cowland, J. B., & Borregaard, N. (2005) · Blood · doi:10.1182/blood-2004-08-3346 · Cited by 281 · see citing works
Carotta, S., Dakic, A., D'Amico, A., Pang, S. H. M., Greig, K. T., Nutt, S. L., & Wu, L. (2010) · Immunity · doi:10.1016/j.immuni.2010.05.005 · Cited by 279 · see citing works
Positive Feedback Between PU.1 and the Cell Cycle Controls Myeloid Differentiation
Kueh, H. Y., Champhekar, A., Nutt, S. L., Elowitz, M. B., & Rothenberg, E. V. (2013) · Science · doi:10.1126/science.1240831 · Cited by 273 · see citing works
Rosenbauer, 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
Spooner, C. J., Cheng, J. X., Pujadas, E., Laslo, P., & Singh, H. (2009) · Immunity · doi:10.1016/j.immuni.2009.07.011 · Cited by 188 · see citing works
Self-citationBalance of MafB and PU. 1 specifies alternative macrophage or dendritic cell fate
Bakri, Y., Sarrazin, S., Mayer, U. P., Tillmanns, S., Nerlov, C., Boned, A., & Sieweke, M. H. (2005) · Blood · doi:10.1182/blood-2004-04-1448 · Cited by 187 · see citing works
The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis
Burda, P., Laslo, P., & Stopka, T. (2010) · Leukemia · doi:10.1038/leu.2010.104 · Cited by 184 · 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
Staber, P. B., Zhang, P., Ye, M., Welner, R. S., Nombela-Arrieta, C., Bach, C., Kerenyi, M., Bartholdy, B. A., Zhang, H., Alberich-Jordà, M., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.007 · Cited by 158 · see citing works
IFNγ induces monopoiesis and inhibits neutrophil development during inflammation
de Bruin, A. M., Libregts, S. F., Valkhof, M., Boon, L., Touw, I. P., & Nolte, M. A. (2012) · Blood · doi:10.1182/blood-2011-07-367706 · Cited by 146 · see citing works
Cook, W. D., McCaw, B. J., Herring, C., John, D. L., Foote, S. J., Nutt, S. L., & Adams, J. M. (2004) · Blood · doi:10.1182/blood-2004-06-2234 · Cited by 140 · see citing works
Two distinct auto-regulatory loops operate at the PU.1 locus in B cells and myeloid cells
Leddin, M., Perrod, C., Hoogenkamp, M., Ghani, S., Assi, S., Heinz, S., Wilson, N. K., Follows, G., Schönheit, J., Vockentanz, L., et al. (2011) · Blood · doi:10.1182/blood-2010-08-302976 · Cited by 131 · see citing works
Will, B., Vogler, T. O., Narayanagari, S., Bartholdy, B., Todorova, T. I., da Silva Ferreira, M., Chen, J., Yu, Y., Mayer, J., Barreyro, L., et al. (2015) · Nature Medicine · doi:10.1038/nm.3936 · Cited by 127 · see citing works
Hosokawa, H., Ungerbäck, J., Wang, X., Matsumoto, M., Nakayama, K. I., Cohen, S. M., Tanaka, T., & Rothenberg, E. V. (2018) · Immunity · doi:10.1016/j.immuni.2018.04.024 · Cited by 116 · see citing works
The Transcription Factor PU.1 is a Critical Regulator of Cellular Communication in the Immune System
Turkistany, S. A., & DeKoter, R. P. (2011) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-011-0147-9 · Cited by 96 · see citing works
Visualizing PU.1 activity during hematopoiesis
Back, J., Allman, D., Chan, S., & Kastner, P. (2005) · Experimental Hematology · doi:10.1016/j.exphem.2004.12.010 · Cited by 97 · see citing works
Suh, H. C., Gooya, J., Renn, K., Friedman, A. D., Johnson, P. F., & Keller, J. R. (2006) · Blood · doi:10.1182/blood-2005-06-2216 · Cited by 95 · see citing works
Liang, J., Zhu, F., Cheng, K., Ma, N., Ma, X., Feng, Q., Xu, C., Gao, X., Wang, X., Shi, J., et al. (2023) · Advanced Materials · doi:10.1002/adma.202306158 · Cited by 84 · see citing works
Gupta, P., Gurudutta, G. U., Saluja, D., & Tripathi, R. P. (2009) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2009.00757.x · Cited by 74 · see citing works
PU.1 and Haematopoietic Cell Fate: Dosage Matters
Mak, K. S., Funnell, A. P. W., Pearson, R. C. M., & Crossley, M. (2011) · International Journal of Cell Biology · doi:10.1155/2011/808524 · Cited by 77 · see citing works
Transcription Factors in Eosinophil Development and As Therapeutic Targets
Fulkerson, P. C. (2017) · Frontiers in Medicine · doi:10.3389/fmed.2017.00115 · Cited by 53 · see citing works
Kamath, M. B., Houston, I. B., Janovski, A. J., Zhu, X., Gowrisankar, S., Jegga, A. G., & DeKoter, R. P. (2008) · Leukemia · doi:10.1038/leu.2008.67 · Cited by 41 · see citing works
Functional analysis of PU.1 domains in monocyte‐specific gene regulation
Nishiyama, C., Nishiyama, M., Ito, T., Masaki, S., Masuoka, N., Yamane, H., Kitamura, T., Ogawa, H., & Okumura, K. (2004) · FEBS Letters · doi:10.1016/s0014-5793(04)00116-4 · Cited by 34 · see citing works
Design principles of cell-state-specific enhancers in hematopoiesis
Frömel, R., Rühle, J., Bernal Martinez, A., Szu-Tu, C., Pacheco Pastor, F., Martinez-Corral, R., & Velten, L. (2025) · Cell · doi:10.1016/j.cell.2025.04.017 · Cited by 29 · see citing works
Lentiviral PU.1 overexpression restores differentiation in myeloid leukemic blasts
Durual, S., Rideau, A., Ruault-Jungblut, S., Cossali, D., Beris, P., Piguet, V, & Matthes, T. (2007) · Leukemia · doi:10.1038/sj.leu.2404645 · Cited by 30 · see citing works
A transcription factor PU.1 is critical for Ccl22 gene expression in dendritic cells and macrophages
Yashiro, T., Nakano, S., Nomura, K., Uchida, Y., Kasakura, K., & Nishiyama, C. (2019) · Scientific Reports · doi:10.1038/s41598-018-37894-9 · Cited by 29 · see citing works
Aivalioti, M. M., Bartholdy, B. A., Pradhan, K., Bhagat, T. D., Zintiridou, A., Jeong, J. J., Thiruthuvanathan, V. J., Pujato, M., Paranjpe, A., Zhang, C., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0226 · Cited by 22 · see citing works
“1 protein abundance resulting in enhanced granulocytic lineage differentiation (33).”
BackgroundWhen It Comes to Decisions, Myeloid Progenitors Crave Positive Feedback
Muzzey, D., & van Oudenaarden, A. (2006) · Cell · doi:10.1016/j.cell.2006.08.007 · Cited by 14 · see citing works
Blood stem cell PU.1 upregulation is a consequence of differentiation without fast autoregulation
Ahmed, N., Etzrodt, M., Dettinger, P., Kull, T., Loeffler, D., Hoppe, P. S., Chavez, J. S., Zhang, Y., Camargo Ortega, G., Hilsenbeck, O., et al. (2022) · Journal of Experimental Medicine · doi:10.1084/jem.20202490 · Cited by 9 · see citing works
- Authors
- Dahl, R., Walsh, J. C., Lancki, D., Laslo, P., Iyer, S. R., Singh, H., & Simon, M. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Boston Children's Hospital (US)
- Corresponding author
- Singh, Harinder
- Simon, M Celeste
- Venue
- Nature Immunology
- Published
- 2003-09-07
- Volume
- 4
- Issue
- 10
- Pages
- 1029-1036
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- OpenAlex
- W1972589365
- Cited by
- 380
- References
- 11
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 6 · 2023: 15 · 2022: 10 · 2021: 6 · 2020: 10 · 2019: 22 · 2018: 16 · 2017: 18 · 2016: 26 · 2015: 26 · 2014: 15 · 2013: 17 · 2012: 16
- FWCI
- 8.26
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (2r01hl052094-05a1)
- National Heart, Lung, and Blood Institute (5T32 HL07237, T32HL007237, 5R01HL052094)
- National Institute of General Medical Sciences (5-T32-GM-07151, T32GM007151)
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- PU.1, C/EBPα, granulocyte colony-stimulating factor, macrophage development, neutrophil development, cell fate determination, hematopoietic transcription factors, haploinsufficiency, neutropenia, cytokine signaling, hematopoiesis
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Colony-Forming Units Assay, Hematopoiesis, Hematopoietic Stem Cells, Macrophages, Mice, Inbred C57BL, Neutrophils, Proto-Oncogene Proteins, Trans-Activators, Macrophage Colony-Stimulating Factor, Granulocyte Colony-Stimulating Factor, Mice, Knockout, Cell Lineage, Thyroid Hormone Receptors alpha, 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
