PU.1 induces myeloid lineage commitment in multipotent hematopoietic progenitors
Open accessAbstract
Little is known about the transcription factors that mediate lineage commitment of multipotent hematopoietic precursors. One candidate is the Ets family transcription factor PU.1, which is expressed in myeloid and B cells and is required for the development of both these lineages. We show here that the factor specifically instructs transformed multipotent hematopoietic progenitors to differentiate along the myeloid lineage. This involves not only the up-regulation of myeloid-specific cell surface antigens and the acquisition of myeloid growth-factor dependence but also the down-regulation of progenitor/thrombocyte-specific cell-surface markers and GATA-1. Both effects require an intact PU.1 transactivation domain. Whereas sustained activation of an inducible form of the factor leads to myeloid lineage commitment, short-term activation leads to the formation of immature eosinophils, indicating the existence of a bilineage intermediate. Our results suggest that PU.1 induces myeloid lineage commitment by the suppression of a master regulator of nonmyeloid genes (such as GATA-1) and the concomitant activation of multiple myeloid genes.
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PU.1 regulates lineage-specific gene expression in a dose-dependent manner.
“PU.1 regulates lineage-specific gene expression in a dose-dependent manner21–23.”
From Lymphoid gene expression supports neuroprotective microglia function (2025) · cites this paper as [21]
The Abstract reports that PU.1 activation increases myeloid-specific markers and decreases progenitor-specific markers. The section on the PU.1 transactivation domain reports that stronger PU.1 alleles produce more myeloid differentiation, but says their protein expression levels did not differ. It does not establish that lineage-specific gene expression depends on PU.1 dose. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAll activated macrophages express high levels of RUNX1 and PU.1, thought to be global regulators of macrophage phenotypic expression.
“All activated macrophages, regardless of polarization state, express high levels of the transcription factors runt-related transcription factor 1 (RUNX1) and PU.1, which are thought to represent global regulators of macrophage phenotypic expression [20–22].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [22]
C/EBP-α is known to cooperate with PU.1 in controlling the expression of the GM-CSF receptor.
“Interestingly, C/EBP-α is also known to cooperate with PU.1 in controlling the expression of the GM-CSF receptor [108].”
From PU.1 and partners: regulation of haematopoietic stem cell fate in normal and malignant haematopoiesis (2009) · cites this paper as [108]
During lineage commitment, activation of specific transcription factors directs precursor cells to a particular differentiation pathway.
“During lineage commitment, activation of specific transcription factors has been shown to direct precursor cells to a particular differentiation pathway (3, 41).”
From Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1 (1999) · cites this paper as [41]
GATA-1, PU.1, and C/EBP family members (C/EBPα and C/EBPε in particular) are essential for the commitment and/or terminal differentiation of myeloid progenitors to the eosinophil lineage.
“and C/EBP⑀ in particular) are essential for the commitment and/or terminal differentiation of myeloid progenitors to the eosinophil lineage (1)(2)(3)(4)(5)(6)(7)(8)(9).”
From Novel Combinatorial Interactions of GATA-1, PU.1, and C/EBPε Isoforms Regulate Transcription of the Gene Encoding Eosinophil Granule Major Basic Protein (2002) · cites this paper as [1]
PU.1 acts early to commit multipotential progenitors to the myeloid lineage.
“PU.1 probably plays an important role at several stages in the differentiation process, and there is evidence that it is active at an early stage, mediating commitment of multipotential progenitor cells to the myeloid lineage.8”
From Granulocyte inducer C/EBPα inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions (2002) · cites this paper as [8]
PU.1 instructs transformed chicken multipotent hematopoietic progenitors to differentiate along the myeloid lineage.
“PU.1 has been demonstrated to instruct transformed chicken multipotent hematopoietic progenitors to differentiate along the myeloid lineage.8”
From Granulocyte inducer C/EBPα inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions (2002) · cites this paper as [8]
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“1 in Myb-Ets-transformed multipotent progenitor cells induces the formation of cells with properties of immature eosinophils after short-term culture.(21) The mechanism by which PU.”
BackgroundReddy, 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
The genomic landscapes of inflammation
Natoli, G., Ghisletti, S., & Barozzi, I. (2011) · Genes & Development · doi:10.1101/gad.2018811 · Cited by 152 · see citing works
“Although Bcl-6 is considered mainly a developmental regulator, it is responsive to extracellular cues (Bereshchenko et al. 2002; Pantano et al. 2006).”
BackgroundHaemopedia RNA-seq: a database of gene expression during haematopoiesis in mice and humans
Choi, J., Baldwin, T., Wong, M., Bolden, J. E., Fairfax, K., Lucas, E. C., Cole, R., Biben, C., Morgan, C., Ramsay, K., et al. (2018) · Nucleic Acids Res. · doi:10.1093/nar/gky1020 · Cited by 151 · see citing works
Hertel, C., Zhou, X.-G., Hamilton-Dutoit, S., & Junker, S. (2002) · Oncogene · doi:10.1038/sj.onc.1205629 · Cited by 148 · see citing works
“3*PU.1-Luc is from Nerlov and Graf (1998).”
Mast cells and eosinophils: the two key effector cells in allergic inflammation
Minai-Fleminger, Y., & Levi-Schaffer, F. (2009) · Inflammation Research · doi:10.1007/s00011-009-0042-6 · Cited by 143 · see citing works
“Eosinophils differentiate and undergo trafficking under the regulation of the transcription factors GATA-1&2, and c/EBP, the chemokine eotaxin, and the CD4? Th2 cell-derived survival cytokines IL-3, IL-5 and GM-CSF [5, 14, 21–26].”
BackgroundThe key role of PU.1/SPI-1 in B cells, myeloid cells and macrophages
Lloberas, J., Soler, C., & Celada, A. (1999) · Immunology Today · doi:10.1016/s0167-5699(99)01442-5 · Cited by 142 · see citing works
Heyworth, C., Pearson, S., May, G., & Enver, T. (2002) · EMBO Journal · doi:10.1093/emboj/cdf368 · Cited by 141 · see citing works
A blueprint for engineering cell fate: current technologies to reprogram cell identity
Morris, S. A., & Daley, G. (2013) · Cell Research · doi:10.1038/cr.2013.1 · Cited by 139 · see citing works
EGO, a novel, noncoding RNA gene, regulates eosinophil granule protein transcript expression.
Wagner, L. A., Christensen, C. J., Dunn, D., Spangrude, G., Georgelas, A., Kelley, L., Esplin, M., Weiss, R., & Gleich, G. (2007) · Blood · doi:10.1182/blood-2006-06-027987 · Cited by 138 · see citing works
A disease-associated gene desert directs macrophage inflammation through ETS2
Stankey, C., Bourges, C., Haag, L., Turner-Stokes, T., Piedade, A., Palmer-Jones, C., Papa, I., dos Santos, M. S., Zhang, Q., Cameron, A., et al. (2024) · Nature · doi:10.1038/s41586-024-07501-1 · Cited by 136 · see citing works
Regulation of granulopoiesis by transcription factors and cytokine signals
Ward, A. C., Loeb, D., Soede-Bobok, A. A., Touw, I., & Friedman, A. (2000) · Leukemia · doi:10.1038/sj.leu.2401808 · Cited by 131 · see citing works
Making Eosinophils Through Subtle Shifts in Transcription Factor Expression
McNagny, K., & Graf, T. (2002) · Journal of Experimental Medicine · doi:10.1084/jem.20020636 · Cited by 133 · see citing works
“1 induces these cells to mature into myeloblasts through a complete down-regulation of GATA-1 (12).”
BackgroundSelf-citationHematopoietic developmental pathways: on cellular basis
Iwasaki, H., & Akashi, K. (2007) · Oncogene · doi:10.1038/sj.onc.1210754 · Cited by 132 · see citing works
“1 and GATA-1 mutually inhibit each other’s expression and transactivation functions (Nerlov and Graf, 1998; Rekhtman et al., 1999; Zhang et al., 1999, 2000; Nerlov et al., 2000; Walsh et al., 2002).”
BackgroundInfluentialCollagen Membrane and Immune Response in Guided Bone Regeneration: Recent Progress and Perspectives
Chu, C., Deng, J., Sun, X., Qu, Y., & Man, Y. (2017) · Tissue Engineering Part B Reviews · doi:10.1089/ten.teb.2016.0463 · Cited by 139 · see citing works
“expressed at high levels to induce and maintain macrophage differentiation (132-134).”
Querfurth, E., Schuster, M., Kulessa, H., Crispino, J., Döderlein, G., Orkin, S., Graf, T., & Nerlov, C. (2000) · Genes & Development · doi:10.1101/gad.177200 · Cited by 128 · see citing works
“In the case of PU.1-mediated myeloid commitment, loss of GATA-1 is followed by up-regulation of C/EBP (Nerlov and Graf 1998), which in turn may down-regulate FOG, leading to the wellknown C/EBP +PU.1 no GATA configuration of myeloid cell types.”
BackgroundInfluentialSelf-citationChou, S. T., Khandros, E., Bailey, L. C., Nichols, K., Vakoc, C. R., Yao, Y., Huang, Z., Crispino, J., Hardison, R., Blobel, G., et al. (2009) · Blood · doi:10.1182/blood-2009-03-207944 · Cited by 126 · see citing works
Transcriptional programming of the dendritic cell network
Belz, G. T., & Nutt, S. L. (2012) · Nature reviews. Immunology · doi:10.1038/nri3149 · Cited by 282 · see citing works
Gierlikowska, B., Stachura, A., Gierlikowski, W., & Demkow, U. A. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.666732 · Cited by 134 · see citing works
“Role in Health Neutrophils are produced in the venous sinuses of the bone marrow, where they derive from a common myeloid progenitor cells (Figure 1; Nerlov and Graf, 1998).”
BackgroundStein, S. J., & Baldwin, A. (2013) · Blood · doi:10.1182/blood-2013-02-486142 · Cited by 121 · see citing works
Du, J., Stankiewicz, M. J., Liu, Y., Xi, Q., Schmitz, J. E., Lekstrom-Himes, J. A., & Ackerman, S. J. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204777200 · Cited by 120 · see citing works
The importance of microglia in the development of the vasculature in the central nervous system
Arnold, T., & Betsholtz, C. (2013) · Vascular Cell · doi:10.1186/2045-824x-5-4 · Cited by 146 · see citing works
“for IL34 in microglial homeostasis [24,27].”
Distinct C/EBP functions are required for eosinophil lineage commitment and maturation
Nerlov, C., McNagny, K. M., Döderlein, G., Kowenz-Leutz, E., & Graf, T. (1998) · Genes & Development · doi:10.1101/gad.12.15.2413 · Cited by 119 · see citing works
“In support of this notion is the finding that activation of a PU.1–ER fusion in MEPs leads to GATA-1 down-regulation followed by myeloid differentiation and that if this process is interrupted at a stage in which cells express an intermediate GATA-1 level, most cells commit to the eosinophil lineage (see Nerlov and Gr…”
BackgroundResultInfluentialSelf-citationPorse, B. T., Bryder, D., Theilgaard-Mönch, K., Hasemann, M. S., Anderson, K., Damgaard, I., Jacobsen, S. E. W., & Nerlov, C. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050067 · Cited by 117 · see citing works
“1 in early myeloid lineage commitment (11).”
Self-citationHosokawa, 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
Moignard, V., Macaulay, I., Swiers, G., Buettner, F., Schütte, J., Calero-Nieto, F., Kinston, S., Joshi, A., Hannah, R., Theis, F. J., et al. (2013) · Nature Cell Biology · doi:10.1038/ncb2709 · Cited by 116 · see citing works
Transcriptional Control of Inflammatory ResponsesPreprint
Smale, S. T., & Natoli, G. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016261 · Cited by 110 · see citing works
“1, an Ets family protein that controls myeloid development and is expressed at very high levels in terminally differentiated macrophages (Scott et al. 1994; Nerlov and Graf 1998).”
BackgroundMacrophages and Cardiovascular Health
Frodermann, V., & Nahrendorf, M. (2018) · Physiological Reviews · doi:10.1152/physrev.00068.2017 · Cited by 126 · see citing works
Oikawa, T., Yamada, T., Kihara-Negishi, F., Yamamoto, H., Kondoh, N., Hitomi, Y., & Hashimoto, Y. (1999) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4400534 · Cited by 109 · see citing works
“1 in multipotent hematopoietic progenitors induces myeloid lineage commitment probably by suppression of a master regulator of nonmyeloid genes.(39) These data suggest that PU.”
BackgroundFOG‐1 and GATA‐1 act sequentially to specify definitive megakaryocytic and erythroid progenitors
Mancini, E., Sanjuán-Pla, A., Luciani, L., Moore, S., Grover, A., Zay, A., Rasmussen, K. D., Luc, S., Bilbao, D., O’Carroll, D., et al. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.390 · Cited by 117 · see citing works
“PU.1 was observed to instruct myeloid differentiation in transformed avian multipotent progenitors while downregulating GATA-1 (Nerlov and Graf, 1998).”
Self-citationEosinophilic gastroenteritis: a review
Oh, H., & Chetty, R. (2008) · Journal of gastroenterology · doi:10.1007/s00535-008-2230-5 · Cited by 107 · see citing works
The gata1/pu.1 lineage fate paradigm varies between blood populations and is modulated by tif1γ
Monteiro, R., Pouget, C., & Patient, R. (2011) · EMBO Journal · doi:10.1038/emboj.2011.34 · Cited by 105 · see citing works
“Consequently, forced expression of gata1 is sufficient to reprogramme myeloid into erythroid cells (Kulessa et al, 1995; Yamaguchi et al, 1998) and conversely overexpression of pu.1 repro- grammes erythroid cells into the myeloid lineage (Nerlov and Graf, 1998).”
Background
- Authors
- Nerlov, C., & Graf, T.
- Affiliations
- European Molecular Biology Laboratory (DE)
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 1998-08-01
- Volume
- 12
- Issue
- 15
- Pages
- 2403-2412
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC317050
- OpenAlex
- W1974612283
- Cited by
- 449
- References
- 46
- Citations by year
- 2026: 13 · 2025: 9 · 2024: 12 · 2023: 16 · 2022: 7 · 2021: 22 · 2020: 18 · 2019: 19 · 2018: 13 · 2017: 21 · 2016: 16 · 2015: 17 · 2014: 15 · 2013: 27 · 2012: 17
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sundhed og Sygdom, Det Frie Forskningsråd
- Medical Research Council
- Topics
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- PU.1, ETS transcription factors, myeloid lineage commitment, hematopoietic progenitor cells, GATA-1, transactivation domain, eosinophils, cell surface markers
- MeSH terms
- Proto-Oncogene Protein Spi-1, Alleles, Animals, Cell Differentiation, Chick Embryo, DNA-Binding Proteins, Hematopoiesis, Hematopoietic Stem Cells, Humans, Proto-Oncogene Proteins, Transcription Factors, Transformation, Genetic, Trans-Activators, Gene Expression Regulation, Developmental, Erythroid-Specific DNA-Binding Factors, GATA1 Transcription Factor
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