Pathway Human Homo sapiens

Transcriptional regulation of granulopoiesis

R-HSA-9616222 in Reactome release 97: under Developmental Biology, with 89 genes placed in it by the mapping files and 0 child pathways in the hierarchy.

The same number in the other species

Reactome writes the mouse and rat events it infers from a human pathway under the human number with the species token. A door opens only where that species' own list in this release holds the id: R-MMU-9616222 (mouse), R-RNO-9616222 (rat). Whether the event was inferred from this one is what the record says.

The record
The genes
Parents and children

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This page reads the pathway's record from its source while you read the rest; with scripts off the card stays at its loading line. Reload with scripts on to see it, or open the source's own page from the link in the card.

01The record

Reactome's own record of this pathway

What this tells you

The pathway list, the hierarchy and the genes on this page are read from the files Reactome publishes for Reactome release 97, built into this site on 2026-09-09: the pathway list, the hierarchy relationship file and the two gene mapping files. The record card is the one live read, Reactome's own record of this pathway.

Reactome's download page describes the mapping files: Mapping files link the source database identifier to the lowest level pathway diagram or subset of the pathway, all levels of the pathway hierarchy or database identifier to all reactions. [R13] The gene list here is the all-levels mapping of NCBI Gene ids, filled from the all-levels mapping of Ensembl ids where the NCBI file has no row for a gene; each row names which file it came from by the shape of its source id. Each row carries the evidence codes the file writes for it, as written and unranked, and both where the file writes both; no page of Reactome's documentation the survey read defines the codes, so this page does not expand them. A gene id the identity files do not name is kept as the source's own id with no door rather than turned into a symbol.

On citing what a search finds, Reactome says: It should be remembered that while we strive to contain the most current and accurate data, Reactome should not be used in citations where other primary sources of information are available. [R12] The record card prints the literature Reactome attaches to a curated pathway for that reason. The data are public domain: All data in the Reactome database and files derived from that data are licensed under the Creative Commons Public Domain Dedication (CC0). User may copy, modify, and distribute these data, even for commercial purposes, without asking for permission. Attribution is encouraged but not required. [R10] The pathway illustrations are licensed apart, under CC BY 4.0, and none is shown here.

A gene on this list is one Reactome places in this pathway in this release, and that is all the row says: it does not say the gene is expressed in a tissue or associated with a disease, which are the other two explorers' questions, read from other sources. Reactome's papers of record are [R01] [R02].

[R01] Ragueneau E, Gong C, Sinquin P, Sevilla C, Beavers D, Grentner A, et al. (2026). The Reactome Knowledgebase 2026. Nucleic Acids Research 54:D673-D681. PMID 41251150, doi 10.1093/nar/gkaf1223.
[R02] Milacic M, Beavers D, Conley P, Gong C, Gillespie M, Griss J, et al. (2024). The Reactome Pathway Knowledgebase 2024. Nucleic Acids Research 52:D672-D678. PMID 37941124, doi 10.1093/nar/gkad1025.
[R10] Reactome, reactome.org. License Agreement. https://reactome.org/license, read 2026-09-09.
[R12] Reactome, reactome.org. Citing us. https://reactome.org/cite, read 2026-09-09.
[R13] Reactome, reactome.org. Download. https://reactome.org/download-data, read 2026-09-09.

Stable id: R-HSA-9616222.3
Class: Pathway
Species: Homo sapiens (human)
Inferred: no: a curated human pathway
Disease pathway: no
Released: 2019-06-12
Events inside: 27, counted from the record

Neutrophilic granulocytes (hereafter called granulocytes) are distinguished by multilobulated nuclei and presence of cytoplasmic granules containing antipathogenic proteins (reviewed in Cowland and Borregaard 2016, Yin and Heit 2018). Granulocytes comprise eosinophils, basophils, mast cells, and neutrophils, all of which are ultimately derived from hemopoietic stem cells (HSCs), a self-renewing population of stem cells located in the bone marrow. A portion of HSCs exit self-renewing proliferation and differentiate to form multipotent progenitors (MPPs). MPPs then differentiate to form common myeloid progenitors (CMPs) as well as the erythrocyte lineage. CMPs further differentiate into granulocyte-monocyte progenitors (GMPs) which can then differentiate into monocytes or any of the types of granulocytes (reviewed in Fiedler and Brunner 2012). granulocytes are the most abundant leukocytes in peripheral blood.

For early granulopoiesis the CEBPA, SPI1 (PU.1), RAR, CBF, and MYB transcription factors are essential. CEBPE, SPI1, SP1, CDP, and HOXA10 transcription factors initiate terminal neutrophil differentiation.

Initially, RUNX1 activates SPI1 (PU.1), which is believed to be the key transcription factor driving the formation of MPPs and CMPs (reviewed in Friedman 2007, Fiedler and Brunner 2012). SPI1, in turn, activates expression of CEBPA, an indispensable transcription factor for granulopoiesis especially important in the transition from CMP to GMP (inferred from mouse homologs in Wilson et al. 2010, Guo et al. 2012, Guo et al. 2014, Cooper et al. 2015). CEBPA, in turn, activates the expression of several transcription factors and receptors characteristic of granulocytes, including CEBPA (autoregulation), CEBPE (Loke et al. 2018, and inferred from mouse homologs in Wang and Friedman 2002, Friedman et al. 2003), GFI1 (inferred from mouse homologs in Lidonnici et al. 2010), KLF5 (Federzoni et al. 2014), IL6R (inferred from mouse homologs in Zhang et al. 1998), and CSF3R (Smith et al. 1996). Importantly, CEBPA dimers repress transcription of MYC (c-Myc) (Johansen et al. 2001, and inferred from mouse homologs in Slomiany et al. 2000, Porse et al. 2001). CEBPA binds CDK2 and CDK4 (Wang et al. 2001) which inhibits their kinase activity by disrupting their association with cyclins thereby limiting proliferation and favoring differentiation of granulocyte progenitors during regular ("steady-state") granulopoiesis (reviewed in Friedman 2015). The transcription factor GFI1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1 (de la Luz Sierra et al. 2010).

Inhibitors of DNA binding (ID) proteins ID1 and ID2 regulate granulopoiesis and eosinophil production such that ID1 induces neutrophil development and inhibits eosinophil differentiation, whereas ID2 induces both eosinophil and neutrophil development (Buitenhuis et al. 2005, Skokowa et al. 2009).

Major infection activates emergency granulopoiesis (reviewed in Manz and Boettcher 2014, Hirai et al. 2015), the production of large numbers of granulocytes in a relatively short period of time. Emergency granulopoiesis is activated by cytokines, CSF2 (GM-CSF) and especially CSF3 (G-CSF, reviewed in Panopoulos and Watowich 2008, Liongue et al. 2009) which bind receptors, CSF2R and CSF3R, respectively, resulting in expression of CEBPB, which interferes with repression of MYC by CEBPA (inferred from mouse homologs in Zhang et al. 2010) and represses MYC less than CEBPA does (Hirai et al. 2006), leading to proliferation of granulocyte progenitors prior to final differentiation.Both, emergency and steady-state granulopoiesis are regulated by direct interaction of CEBPA (steady-state) or CEBPB (emergency) proteins with NAD+-dependent protein deacetylases, SIRT1 and SIRT2 (Skokowa et al. 2009). G-CSF induces the NAD+-generating enzyme, Nicotinamide phosphoribosyltransferase (NAMPT, or PBEF), that in turn activates sirtuins (Skokowa et al. 2009).

GADD45A and GADD45B proteins are essential for stress-induced granulopoiesis and granulocyte chemotaxis by activation of p38 kinase (Gupta et al. 2006, Salerno et al. 2012). SHP2 is required for induction of CEBPA expression and granulopoiesis in response to CSF3 (G-CSF) or other cytokines independent of SHP2-mediated ERK activation (Zhang et al. 2011).

Transcription of neutrophil granule proteins (e.g. ELANE, MPO, AZU1, DEFA4), that play an essential role in bacterial killing are regulated by CEBPE and SPI1 (PU.1) transcription factors (Gombart et al. 2003, Nakajima et al. 2006). RUNX1 and LEF1 also regulate ELANE (ELA2) mRNA expression by binding to its promoter (Li et al. 2003).

Literature Reactome attaches

The role of transcription factors in the guidance of granulopoiesisAm J Blood Res, 2012, vol. 2, p. 57-65PubMed 22432088
Transcriptional Regulation of Emergency Granulopoiesis in LeukemiaFront Immunol, 2018, vol. 9, p. 481PubMed 29593731
Non-steady-state hematopoiesis regulated by the C/EBPβ transcription factorCancer Sci., 2015, vol. 106, p. 797-802PubMed 25940801
C/EBPα in normal and malignant myelopoiesisInt. J. Hematol., 2015, vol. 101, p. 330-41PubMed 25753223
Transcriptional control of granulocyte and monocyte developmentOncogene, 2007, vol. 26, p. 6816-28PubMed 17934488
Combinatorial transcriptional control in blood stem/progenitor cells: genome-wide analysis of ten major transcriptional regulatorsCell Stem Cell, 2010, vol. 7, p. 532-44PubMed 20887958
The +37 kb Cebpa Enhancer Is Critical for Cebpa Myeloid Gene Expression and Contains Functional Sites that Bind SCL, GATA2, C/EBPα, PU.1, and Additional Ets FactorsPLoS ONE, 2015, vol. 10, p. e0126385

Reactome's record lists 9 orthologous events, R-RNO-9616222 (Rattus norvegicus), R-MMU-9616222 (Mus musculus) among the species this site serves, and 7 in species this site opens no page for.

Reactome ContentService, this pathway's record · Reactome v97 · read 2026-09-30 ET · Reactome pathway browser"Transcriptional regulation of granulopoiesis". Reactome, release 97, https://reactome.org/PathwayBrowser/#/R-HSA-9616222 with StableID: R-HSA-9616222.3 (accessed 2026-09-30 ET). Reactome version 97 (CC0).

Reading this pathway's record from Reactome (the pathway record).Still reading. A first read of a pathway can take a while; this page waits up to 35 seconds for it, and its scripts then bring in the panel, or a line saying what did not arrive.

02The genes

Genes Reactome places in this human pathway

The mapping files place 89 genes in this human pathway; showing 1 to 89, in pages of 100, sorted by symbol for reading. The order carries no ranking.

Genes Reactome places in this human pathway, page 1 of 1
Gene	Authority id	Mapping file id	Evidence codes
GeneCBFB	AuthorityHGNC:1539	Mapping file id865 NCBI file	EvidenceIEA
GeneCDK2	AuthorityHGNC:1771	Mapping file id1017 NCBI file	EvidenceTAS
GeneCDK4	AuthorityHGNC:1773	Mapping file id1019 NCBI file	EvidenceTAS
GeneCDKN1A	AuthorityHGNC:1784	Mapping file id1026 NCBI file	EvidenceTAS
GeneCEBPA	AuthorityHGNC:1833	Mapping file id1050 NCBI file	EvidenceIEA, TAS
GeneCEBPB	AuthorityHGNC:1834	Mapping file id1051 NCBI file	EvidenceIEA
GeneCEBPE	AuthorityHGNC:1836	Mapping file id1053 NCBI file	EvidenceIEA
GeneCREB1	AuthorityHGNC:2345	Mapping file id1385 NCBI file	EvidenceIEA
GeneCSF3R	AuthorityHGNC:2439	Mapping file id1441 NCBI file	EvidenceIEA
GeneDEK	AuthorityHGNC:2768	Mapping file id7913 NCBI file	EvidenceIEA, TAS
GeneE2F1	AuthorityHGNC:3113	Mapping file id1869 NCBI file	EvidenceIEA, TAS
GeneEP300	AuthorityHGNC:3373	Mapping file id2033 NCBI file	EvidenceIEA, TAS
GeneFLI1	AuthorityHGNC:3749	Mapping file id2313 NCBI file	EvidenceIEA
GeneGATA2	AuthorityHGNC:4171	Mapping file id2624 NCBI file	EvidenceIEA
GeneGFI1	AuthorityHGNC:4237	Mapping file id2672 NCBI file	EvidenceIEA
GeneH2AB1	AuthorityHGNC:22516	Mapping file id474382 NCBI file	EvidenceIEA
GeneH2AC14	AuthorityHGNC:4727	Mapping file id8331 NCBI file	EvidenceIEA
GeneH2AC18	AuthorityHGNC:4736	Mapping file id8337 NCBI file	EvidenceIEA
GeneH2AC19	AuthorityHGNC:29668	Mapping file id723790 NCBI file	EvidenceIEA
GeneH2AC20	AuthorityHGNC:4738	Mapping file id8338 NCBI file	EvidenceIEA
GeneH2AC4	AuthorityHGNC:4734	Mapping file id8335 NCBI file	EvidenceIEA
GeneH2AC6	AuthorityHGNC:4733	Mapping file id8334 NCBI file	EvidenceIEA
GeneH2AC7	AuthorityHGNC:4729	Mapping file id3013 NCBI file	EvidenceIEA
GeneH2AC8	AuthorityHGNC:4724	Mapping file id3012 NCBI file	EvidenceIEA
GeneH2AJ	AuthorityHGNC:14456	Mapping file id55766 NCBI file	EvidenceIEA
GeneH2AX	AuthorityHGNC:4739	Mapping file id3014 NCBI file	EvidenceIEA
GeneH2AZ2	AuthorityHGNC:20664	Mapping file id94239 NCBI file	EvidenceIEA
GeneH2BC1	AuthorityHGNC:18730	Mapping file id255626 NCBI file	EvidenceIEA
GeneH2BC10	AuthorityHGNC:4756	Mapping file id8346 NCBI file	EvidenceIEA
GeneH2BC11	AuthorityHGNC:4761	Mapping file id8970 NCBI file	EvidenceIEA
GeneH2BC12	AuthorityHGNC:13954	Mapping file id85236 NCBI file	EvidenceIEA
GeneH2BC12L	AuthorityHGNC:4762	Mapping file id54145 NCBI file	EvidenceIEA
GeneH2BC13	AuthorityHGNC:4748	Mapping file id8340 NCBI file	EvidenceIEA
GeneH2BC14	AuthorityHGNC:4750	Mapping file id8342 NCBI file	EvidenceIEA
GeneH2BC15	AuthorityHGNC:4749	Mapping file id8341 NCBI file	EvidenceIEA
GeneH2BC17	AuthorityHGNC:4758	Mapping file id8348 NCBI file	EvidenceIEA
GeneH2BC21	AuthorityHGNC:4760	Mapping file id8349 NCBI file	EvidenceIEA
GeneH2BC26	AuthorityHGNC:20514	Mapping file id128312 NCBI file	EvidenceIEA
GeneH2BC3	AuthorityHGNC:4751	Mapping file id3018 NCBI file	EvidenceIEA
GeneH2BC4	AuthorityHGNC:4757	Mapping file id8347 NCBI file	EvidenceIEA
GeneH2BC5	AuthorityHGNC:4747	Mapping file id3017 NCBI file	EvidenceIEA
GeneH2BC6	AuthorityHGNC:4753	Mapping file id8344 NCBI file	EvidenceIEA
GeneH2BC7	AuthorityHGNC:4752	Mapping file id8343 NCBI file	EvidenceIEA
GeneH2BC8	AuthorityHGNC:4746	Mapping file id8339 NCBI file	EvidenceIEA
GeneH2BC9	AuthorityHGNC:4755	Mapping file id8345 NCBI file	EvidenceIEA
GeneH3-3A	AuthorityHGNC:4764	Mapping file id3020 NCBI file	EvidenceIEA
GeneH3-3B	AuthorityHGNC:4765	Mapping file id3021 NCBI file	EvidenceIEA
GeneH3C1	AuthorityHGNC:4766	Mapping file id8350 NCBI file	EvidenceIEA
GeneH3C10	AuthorityHGNC:4775	Mapping file id8357 NCBI file	EvidenceIEA
GeneH3C11	AuthorityHGNC:4771	Mapping file id8354 NCBI file	EvidenceIEA
GeneH3C12	AuthorityHGNC:4774	Mapping file id8356 NCBI file	EvidenceIEA
GeneH3C13	AuthorityHGNC:25311	Mapping file id653604 NCBI file	EvidenceIEA
GeneH3C14	AuthorityHGNC:20503	Mapping file id126961 NCBI file	EvidenceIEA
GeneH3C15	AuthorityHGNC:20505	Mapping file id333932 NCBI file	EvidenceIEA
GeneH3C2	AuthorityHGNC:4776	Mapping file id8358 NCBI file	EvidenceIEA
GeneH3C3	AuthorityHGNC:4768	Mapping file id8352 NCBI file	EvidenceIEA
GeneH3C4	AuthorityHGNC:4767	Mapping file id8351 NCBI file	EvidenceIEA
GeneH3C6	AuthorityHGNC:4769	Mapping file id8353 NCBI file	EvidenceIEA
GeneH3C7	AuthorityHGNC:4773	Mapping file id8968 NCBI file	EvidenceIEA
GeneH3C8	AuthorityHGNC:4772	Mapping file id8355 NCBI file	EvidenceIEA
GeneH4C1	AuthorityHGNC:4781	Mapping file id8359 NCBI file	EvidenceIEA
GeneH4C11	AuthorityHGNC:4785	Mapping file id8363 NCBI file	EvidenceIEA
GeneH4C12	AuthorityHGNC:4784	Mapping file id8362 NCBI file	EvidenceIEA
GeneH4C13	AuthorityHGNC:4791	Mapping file id8368 NCBI file	EvidenceIEA
GeneH4C14	AuthorityHGNC:4794	Mapping file id8370 NCBI file	EvidenceIEA
GeneH4C15	AuthorityHGNC:29607	Mapping file id554313 NCBI file	EvidenceIEA
GeneH4C16	AuthorityHGNC:20510	Mapping file id121504 NCBI file	EvidenceIEA
GeneH4C2	AuthorityHGNC:4789	Mapping file id8366 NCBI file	EvidenceIEA
GeneH4C3	AuthorityHGNC:4787	Mapping file id8364 NCBI file	EvidenceIEA
GeneH4C4	AuthorityHGNC:4782	Mapping file id8360 NCBI file	EvidenceIEA
GeneH4C5	AuthorityHGNC:4790	Mapping file id8367 NCBI file	EvidenceIEA
GeneH4C6	AuthorityHGNC:4783	Mapping file id8361 NCBI file	EvidenceIEA
GeneH4C8	AuthorityHGNC:4788	Mapping file id8365 NCBI file	EvidenceIEA
GeneH4C9	AuthorityHGNC:4793	Mapping file id8294 NCBI file	EvidenceIEA
GeneIL6R	AuthorityHGNC:6019	Mapping file id3570 NCBI file	EvidenceIEA
GeneKLF5	AuthorityHGNC:6349	Mapping file id688 NCBI file	EvidenceIEA
GeneKMT2A	AuthorityHGNC:7132	Mapping file id4297 NCBI file	EvidenceIEA
GeneLEF1	AuthorityHGNC:6551	Mapping file id51176 NCBI file	EvidenceIEA, TAS
GeneMYB	AuthorityHGNC:7545	Mapping file id4602 NCBI file	EvidenceIEA
GeneMYC	AuthorityHGNC:7553	Mapping file id4609 NCBI file	EvidenceIEA
GenePML	AuthorityHGNC:9113	Mapping file id5371 NCBI file	EvidenceIEA, TAS
GeneRARA	AuthorityHGNC:9864	Mapping file id5914 NCBI file	EvidenceIEA, TAS
GeneRUNX1	AuthorityHGNC:10471	Mapping file id861 NCBI file	EvidenceIEA
GeneRXRA	AuthorityHGNC:10477	Mapping file id6256 NCBI file	EvidenceIEA, TAS
GeneSPI1	AuthorityHGNC:11241	Mapping file id6688 NCBI file	EvidenceIEA, TAS
GeneSTAT3	AuthorityHGNC:11364	Mapping file id6774 NCBI file	EvidenceIEA
GeneTAL1	AuthorityHGNC:11556	Mapping file id6886 NCBI file	EvidenceIEA
GeneTFDP1	AuthorityHGNC:11749	Mapping file id7027 NCBI file	EvidenceIEA, TAS
GeneTFDP2	AuthorityHGNC:11751	Mapping file id7029 NCBI file	EvidenceIEA, TAS

Evidence codes on this page: IEA, TAS, as the mapping file writes them; a row carrying two was written twice by the file, once under each. The mapping file id says which file placed the gene: an NCBI Gene id from NCBI2Reactome_All_Levels.txt, an Ensembl gene id from Ensembl2Reactome_All_Levels.txt. The two files can disagree about a code, so a row's codes are the one file's view. Measured by this site's build over this release on 2026-09-09: of the 138,908 human pathway-gene pairs both files place, 207 (0.149 per cent, over 47 genes) carry TAS in the Ensembl file where the NCBI rows carry IEA alone.

Reactome mapping files, the human rows for this pathway · Reactome release 97 · read 2026-09-09 · Reactome downloads"NCBI2Reactome_All_Levels.txt" and "Ensembl2Reactome_All_Levels.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.

03The hierarchy

Parents and children in this release's hierarchy

Parents

Developmental BiologyR-HSA-12667381,589 genes

Children

None: no pathway of this release's list names this one as a parent.

Reactome's hierarchy is a graph rather than a tree: a pathway can sit under more than one parent, and the gene counts are each pathway's own placements at every level under it, so a parent's count is not the sum of its children's.

Reactome, the human pathway list and hierarchy relationship file · Reactome release 97 · read 2026-09-09 · Reactome downloads"ReactomePathways.txt" and "ReactomePathwaysRelation.txt", Reactome, release 97, https://reactome.org/download-data/ (date of access 2026-09-09). Data CC0; attribution encouraged.