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Oncogene (2007) 26, 6816–6828 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Transcriptional control of and development

AD Friedman

Division of Pediatric Oncology, Johns Hopkins University, Baltimore, MD, USA

PU.1 directs the to the lymphoid- progenitor (GMP; Akashi et al., 2000; Traver et al., 2001). myeloid progenitor (LMP) and interacts with GATA- The GMP population includes granulocyte-, monocyte- and binding 1 to inhibit commitment to the mega- predominantly granulocyte/monocyte-colony forming units karyocyte-erythroid progenitor. The CCAAT/- (CFU-G, CFU-M and CFU-GM). CFU-G and CFU-M binding protein (C/EBP)a then directs the LMP to the likely arise from CFU-GM, though direct development of granulocyte-monocyte progenitor (GMP) stage, while CFU-M or CFU-G from CMP or HSC under some inhibiting lymphoid development via cross-inhibition of circumstances remains a formal possibility. GMPs also arise Pax5 and potentially other regulators. Increased PU.1 from a linÀKit þ Sca þ IL7Raþ CD34 þ Flt3 þ lymphoid-mye- activity favors monocytic commitment of the GMP. loid progenitor (LMP; Adolfsson et al., 2005). Fetalliverand Induction of PU.1 by C/EBPa and interaction of PU.1 adult marrow also harbor cells with combined B-lineage and with c-Jun elevates PU.1 activity. Zippering of C/EBPa monocyte/ potential(Lacaud et al., 1998; with c-Jun or c-Fos also contributes to monocyte lineage Montecino-Rodriguez et al., 2001; Traver et al., 2001). specification. An additional factor, potentially an Id1- not only develop into , but in regulated basic helix–loop–helix protein, may be required addition give rise to and myeloid dendritic cells for the GMP to commit to the granulocyte lineage. Egr-1, (Roodman, 1996; Manz et al., 2001). Egr-2, , MafB/c: Fos and PU.1:in- An earlier review provided an overview of the terferon regulatory factor 8 complexes direct further transcriptionalregulation of immature and mature monocytic maturation, while (RAR) granulocyte and monocyte lineage-specific (Fried- and C/EBPe direct . Both C/EBPa and man, 2002). From that survey, it was apparent that RARs induce C/EBPe, and PU.1 is also required, albeit at CCAAT/enhancer-binding (C/EBPs) and PU.1 lower levels, for granulocytic maturation. HoxA10 and regulate the large majority of myeloid genes and that CAAT displacement protein act as transcriptional repres- AP-1 proteins activate at least a subset of monocytic sors to delay expression of terminal differentiation. Gfi-1 genes. Although Runx1 and c-Myb regulate several and Egr-1,2/Nab2 complexes repress each other to genes in immature myeloid cells, they likely play a maintain myeloid lineage fidelity. NF-jB directly binds greater role in HSC biology. The current review will and cooperates with C/EBPb to induce the inflammatory focus on progress over the last 5 years on regulation of response in mature myeloid cells and potentially also myeloid lineage development by C/EBPa and PU.1 and cooperates with C/EBPa to regulate early . by transcription factors and signals that Oncogene (2007) 26, 6816–6828; doi:10.1038/sj.onc.1210764 interact directly or indirectly with these factors or further downstream in granulocyte or monocyte lineage Keywords: granulocyte; monocyte; differentiation; C/EBPa; development. PU.1

CCAAT/enhancer-binding protein a, b and e

Introduction The C/EBPs homo- and heterodimerize via their C-terminalleucine zipper (LZ) domains and bind DNA Polymorphonuclear and mononuclear func- as obligate dimers via the adjacent basic regions (BR) tion in host defense against infections and recognize, (Landschulz et al., 1989). The co-crystalstructure of the ingest and destroy foreign materials and organisms. C/EBPa BR-LZ (bZIP) domain with its cognate binding Pluripotent hematopoietic stem cells (HSC) give rise to a site confirms that the bZIP domain is a continuous linÀIL7RaÀKit þ Sca-1ÀCD34 þ FcgRlo common myeloid a-helix with residues 286–300 entering the major groove progenitor (CMP), which in turn gives rise to a to make direct contact with the base pairs and the linÀIL7RaÀKit þ Sca-1ÀCD34 þ FcgRhi granulocyte-monocyte phosphate backbone (Miller et al., 2003). The consensus binding site is 50-T(T/G)NNGNAA(T/G)-30. C/EBPa, C/EBPb and C/EBPd have N-terminal trans-activation Correspondence: Dr AD Friedman, Division of Pediatric Oncology, Johns Hopkins University, Cancer Research Building I, Room 253, domains, and translation initiation from internal methio- 1650 Orleans Street, Baltimore, MD 21231, USA. nines produces truncated, dominant-inhibitory polypep- E-mail: [email protected] tides that retain the bZIP domain, but have an altered Myeloid development AD Friedman 6817 spectrum of preferred DNA-binding sites (Friedman C/EBPa–ER fusion protein even in cycloheximide, sug- et al., 1989; Friedman and McKnight, 1990; Descombes gesting direct activation (Wang et al., 1999). Indeed, and Schibler, 1991; Lin et al., 1993; Calkhoven et al., C/EBPa binds and activates the PU.1 and distal 2000; Cleaves et al., 2004). The Notch-induced protein enhancer, and the role of this activation in myelopoiesis Trib2 binds the 42 kDa but not the 30 kDa isoform of will be discussed further below (Kummalue and Friedman, C/EBPa to induce its proteasome-mediated degradation 2003; Yeamans et al., 2007). C/EBPe(À/À) mice develop (Keeshan et al., 2006). Phosphorylation of C/EBPa all of the hematopoietic lineages, but have a defect in serine 21 by extracellular signal-regulated kinase sup- terminalneutrophilmaturation resemblinghuman cases of presses its activity (Ross et al., 2004). C/EBPe has both secondary deficiency (SGD; Yamanaka et al., trans-activation and trans-repression domains and is 1997; Chumakov et al., 1997), and cases of SGD expressed as several alternatively spliced isoforms harboring C/EBPe point have been described (Williamson et al., 1998; Lekstrom-Himes, 2001). (Lekstrom-Himes et al., 1999; Gombart et al., 2001). Within hematopoiesis, C/EBPa, C/EBPb and C/EBPd Defects in macrophage function are also present in are predominantly expressed in the granulocyte, mono- C/EBPe(À/À) mice (Gombart et al., 2005). C/EBPa binds cyte and eosinophillineages(Scott et al., 1992; Muller the promoter of micro-RNA 223, which in turn suppresses et al., 1995; Radomska et al., 1998). C/EBPa expression translation of -A to favor granulocytic predominates in immature cells and is detected in the maturation (Fazi et al., 2005). C/EBPa also binds and HSC, CMP and GMP, but not the common lymphoid activates its own promoter, perhaps reflecting a feed- (CLP) or megakeryocyte-erythroid progenitor (MEP) forward mechanism to fix commitment decisions (Christy populations (Traver et al., 2001). C/EBPe is found in et al., 1991). As a further means of stabilizing commitment later-stage (Antonson et al., 1996). CHOP, decisions, cross-inhibition of C/EBPa and Pax5 expression a dominant-inhibitory C/EBP isoform is not expressed may stabilize transition of LMP to either the CLP or during normalgranulopoiesis, but is induced by DNA GMP stages, although the extent of such competition and damage or ER- and participates in the inflamma- the mechanisms involved require further investigation tory response (Friedman, 1996; Endo et al., 2006). (Heavey et al., 2003; Xie and Graf, 2004; Hsu et al., 2006; C/EBPa(À/À) neonatalmice lackneutrophilsand Anderson et al., 2007). Pax5 also represses the MCSFR ; although they retain monocytes in their promoter through direct interaction (Tagoh et al., 2006). peripheralblood, Mac-1 þ /Gr-1À monocytes are reduced Under some circumstances, C/EBPb can compensate in their fetaland newborn livers, and marrow CFU-M for loss of C/EBPa during myelopoiesis. Expression of numbers are reduced twofold despite expression of the C/EBPb from the C/EBPa locus leads to normal macrophage colony stimulating factor receptor hematopoiesis (Jones et al., 2002). C/EBPa(À/À) fetal (MCSFR; Zhang et al., 1997). Consistent with these liver cells exposed in vivo to GM-CSF and IL-3 generate observations, Mx1-CRE-mediated deletion of C/EBPa , whereas knockdown of C/EBPb in these in adult mice results in a block of the CMP to GMP cells reduces their ability to do so (Hirai et al., 2006). transition (Zhang et al., 2004). A separate study C/EBPb(À/À) marrow cells generate 25–50% reduced investigated myelopoiesis in independently generated numbers of myeloid colonies compared with C/EBPa(À/À) mice similarly concludes that lack of C/EBPb( þ /À) cells in various cytokine conditions, C/EBPa leads to a block between the CMP and GMP and the colonies formed are smaller, potentially reflect- stage, based on increased CFU-S but reduced CFU-GM, ing an ability of C/EBPb to stimulate the proliferation neutrophils and monocyte/macrophages (Heath et al., of myeloid cells, as has been seen with other cell types 2004). Lack of myelopoiesis in vivo from C/EBPa(À/À) (Hirai et al., 2006; Sebastian and Johnson, 2006). progenitors may in part reflect reduced expression of the Induction of C/EBPb in vitro may account for the M-CSF and G-CSF Receptors, as each of their ability of C/EBPa(À/À) cells cultured in IL-3 or GM- promoters depends upon C/EBPa for expression (Zhang CSF, or transduced with the G-CSF receptor and et al., 1994; Smith et al., 1996). A global inhibitor of cultured in G-CSF, to generate neutrophils (Zhang C/EBP-induced trans-activation, KRAB-C/EBPa-ER, et al., 1998, 2002). inhibits murine CFU-G, CFU-M and CFU-GM forma- In contrast to C/EBPb, C/EBPa potently inhibits G1 tion in (IL)-3 or GM-CSF and prevents 32Dcl3 to S progression in a variety of lineages, granulocytic differentiation even in the presence of including myeloid cells (Umek et al., 1991; Wang et al., exogenous G-CSF receptor, indicating that C/EBP family 1999). C/EBPa inhibits cell proliferation via several members are required subsequent to induction of cytokine mechanisms that may vary between cell lineages, receptors for myelopoiesis (Wang and Friedman, 2002). including direct binding of or cyclin-dependent Expression of a dominant inhibitor of C/EBP kinase (cdk)2/cdk4 and induction of p21 (Johnson, DNA-binding in human progenitors similarly prevented 2005). Interaction of E2F1 with the outer surface of the the formation of G-CSF-, M-CSF- or GM-CSF-induced C/EBPa BR enables growth inhibition in myeloid cells myeloid CFUs (Iwama et al., 2002). and is required for their terminaldifferentiation (Porse Beyond regulation lineage-specific genes, such as et al., 2001, 2005; Wang et al., 2003). Repression of the and elastase (Nuchprayoon c- gene by C/EBPa requires tethering of C/EBPa to et al., 1994; Ford et al., 1996; Oelgeschla¨ ger et al., 1996), the c-Myc promoter via DNA-bound E2F1 (Johansen PU.1 and C/EBPe are two regulatory transcription et al., 2001). The N terminus of C/EBPa is required for factors whose mRNAs are rapidly induced by the its E2F1-dependent cell cycle inhibition, potentially via

Oncogene Myeloid development AD Friedman 6818 interaction with a co-, although further eluci- et al., 1999). Expression of low levels of PU.1 in PU.1(À/À) dation of the mechanism underlying this phenomenon is cells induces granulopoiesis, whereas high levels induce required (Porse et al., 2001). monopoiesis (Dahl et al., 2003; Laslo et al., 2006). Genetic C/EBPa gene knockout studies indicate a block in the analysis also indicates that a higher level of PU.1 favors CMP to GMP transition, but do not address the subse- monocytic over granulocytic development: lack of one PU.1 quent role of C/EBPa in monocyte versus granulocyte allele favors neutrophil development from embryonic stem lineage commitment. The ability of exogenous C/EBPa cells in vitro and encourages neutrophildevelopment in vivo and other C/EBPs to direct granulopoiesis from several in the absence of G-CSF (Dahl et al., 2003); deletion of the myeloid cell lines led to early models depicting a more PU.1 distalenhancer locatedat À14 kb results in 20% of prominent role for C/EBPa during granulopoiesis than normalPU.1 expression and lossof monopoiesis with monopoiesis (Radomska et al., 1998; Wang et al., 1999; preservation of granulopoiesis (Rosenbauer et al., 2004); Wang and Friedman, 2002). However, transduction of and CRE-mediated deletion of PU.1 in adult mice preserves C/EBPa-ER into marrow mononuclear cells followed by granulocytes at the expense of monocytes (Dakic et al., lineage-depletion and then culture with or without 2005). However, the latter two studies found loss of estradiolleadsto the finding that C/EBP a favors MCSFR with preservation of GCSFR expression, leaving formation of monocytes over granulocytes in liquid open the question of whether increased PU.1 favors mono- culture and of CFU-M over CFU-G in methylcellulose poiesis independent of its effect on receptor expression. culture, in IL3/IL-6/SCF or GM-CSF (Wang et al., Investigating why the MCSFR gene is more sensitive 2006). Use of a regulated C/EBPa transgene and lineage to PU.1 levels than the GCSFR gene might provide depletion only after transduction in this protocol mechanistic insight as to why increased PU.1 is required minimizes biases due to lineage-specific cell cycle for monopoiesis. In this regard, PU.1 is sufficient to inhibition. Consistent with the conclusion that C/EBPa reorganize the structure of the MCSFR can direct monopoiesis as well as granulopoiesis, promoter in myeloid progenitors, but requires onset of transduction of B- or T-cell progenitors with C/EBPa Egr-2 expression to fully activate the intronic regulatory induces macrophage but not neutrophildevelopment region designated the FIRE enhancer (Krysinska et al., (Heavey et al., 2003; Xie and Graf, 2004; Laiosa et al., 2007). PU.1 binds and activates its own promoter and 2006); transplantation of mice with marrow transduced distal enhancer, potentially to variable degrees in with C/EBPa increases the proportion of monocytes different lineages and developmental stages dependent from 13 to 88%, while inhibiting (Suh on cooperating factors (Chen et al., 1995b; Okuno et al., et al., 2006); and CLP or MEP isolated from mice 2005). Onset of PU.1 expression in HSC or LMP may expressing a C/EBPa-ER(T) transgene from the H2K depend on Runx1-mediated activation via the PU.1 promoter develop into macrophages upon exposure to distalenhancer (Huang et al., 2007a), with C/EBPa then 4-hydroxytamoxifen (Fukuchi et al., 2006). In contrast, directing LMP or CMP to the GMP stage and beyond, C/EBPa-ER converts CD71 þ erythroid cells to granu- in part, via further PU.1 induction. The C/EBPb and locytes (Cammenga et al., 2003). Perhaps GATA- PU.1 DNA-binding domains directly interact (Yang binding protein 1 (GATA-1), which can directly bind et al., 2000), and promoter-bound C/EBPb increases and inhibit PU.1 (Rekhtman et al., 1999; Zhang et al., PU.1 interaction with a nearby cis element in the IL-1b 1999), prevents monopoiesis in this setting. promoter, augmenting gene induction (Grondin et al., 2007). C/EBPa has the potential to similarly cooperate with PU.1 as these proteins also directly interact (Reddy et al., 2002). Increased PU.1 in myeloid cells may also PU.1 facilitate its ability to directly bind and repress trans- activation by GATA-1 to downmodulate the erythroid PU.1 binds as a monomer to the consensus DNA site program, just as GATA-1 inhibits PU.1 activity in 50-AAAG(A/C/G)GGAAG-30 via its C-terminalEts cooperation with Rb to ensure continued maturation of domain and activates transcription via its N-terminal erythroid and megakaryocytic cells (Rekhtman et al., glutamine-rich and acidic domains (Klemsz et al., 1990). 1999, 2003; Zhang et al., 1999, 2000; Stopka et al., 2005). PU.1 is expressed in B-lymphoid, early T-lymphoid, In addition to favoring monopoiesis over granulopoi- granulocytic and monocytic cells (Klemsz et al., 1990; esis, increased PU.1 expression also favors myeloid over Chen et al., 1995a; Spain et al., 1999). LMP express lymphoid development: expression of exogenous PU.1 in higher levels of PU.1 than MEP (Arinobu et al., 2006). PU.1(À/À) progenitors induces B cells at lower levels PU.1(À/À) mice lack B cells and monocytes and and monocytes at higher levels (DeKoter and Singh, have greatly reduced neutrophils (Scott et al., 1994; 2000); exogenous PU.1 converts B or T cells to McKercher et al., 1996). At the progenitor level, these monocyte/macrophages but not granulocytes (Xie and mice have markedly diminished CLP and GMP Graf, 2004; Dionne et al., 2005; Laiosa et al., 2006); and numbers with increased MEP (Iwasaki et al., 2005). PU.1 knockdown in embryonic stem cell-derived CD34þ Expression of the MCSFR or granulocyte colony cells favors B-cell formation (Zou et al., 2006). The stimulating factor receptor (GCSFR) in PU.1(À/À) ability of both C/EBPs and PU.1 to reprogram lymphoid marrow cells did not rescue myeloid development, cells to the monocyte lineage likely reflects the ability of indicating that PU.1 is required beyond induction of C/EBPs to bind to and activate the PU.1 promoter and these cytokine receptors (DeKoter et al., 1998; Henkel distal enhancer. 32Dcl3 cells, a model of granulocyte

Oncogene Myeloid development AD Friedman 6819 progenitors, differentiates to neutrophils in response to DNA at sites having the 50-TGA(C/G)TCA-30 consen- exogenous C/EBPa-ER but not PU.1-ER, indicating sus. c-Jun, JunB and JunD levels increase during that C/EBPa does more than induce PU.1 to facilitate monocytic maturation, and exogenous c-Fos or c-Jun terminalgranulopoiesis or monopoiesis (Wang et al., induce monocytic differentiation of myeloid cells (Lord 1999). Lack of granulocytic development from lymphoid et al., 1993; Szabo et al., 1994; Li et al., 1994). Phorbol cells transduced with C/EBPa or PU.1 likely reflects their esters, which activate protein kinase C (PKC)s, induce inability to induce a critical cooperating factor in that monocytic maturation of a variety of myeloid cell lines, context. The combination of C/EBPa-ER and exogenous and activated PKCa directs monocytic maturation of GCSFR signals, but not either alone, allows Ba/F3 pro- transduced CFU-GM (Pierce et al., 1998). PKCa B cells to express early myeloid markers, suggesting that activates c-Jun kinase (JNK)2 via direct phosphoryla- unique, myeloid cytokine signals potentiate the response tion of S129, and PKCd phosphorylates S129 of JNK1 to C/EBPa (Wang et al., 2001). Finally, the transition (Lopez-Bergami et al., 2005; Liu et al., 2006). PKCd also from monocyte to Langerhans dendritic cells requires activates JNK via activation of MEKK1, which then downmodulation of C/EBPa with retention of PU.1 kinases MKK7, a JNK kinase (Yoshida et al., 2002). expression (Iwama et al., 2002; Ginhoux et al., 2006). JNK1 and JNK2 are ubiquitous, and their double knockout is embryonic lethal. JNK3 is not present in hematopoietic cells. The JNK inhibitor SP600125 reduces the number of macrophages developing from regulatory factor 8 and interaction with PU.1 murine marrow cells cultured in the presence of M-CSF (Himes et al., 2006). Activated JNK phosphorylates Phosphorylation of PU.1 within its central PEST c-Jun and c-AMP-dependent domain on serine 148 allows interaction with interferon (ATF2), leading to their stabilization. c-Jun:ATF2 regulatory factor 4 (IRF-4) or IRF-8, the latter also trans-activates the c-Fos promoter, and c-Fos:c-Jun designated ICSBP (Eisenbeis et al., 1995; Meraro et al., subsequently induces c-Jun transcription (Shaulian and 1999). IRF-4 and IRF-8 each contain amphipathic Karin, 2001; Weston and Davis, 2002). Perhaps this a-helices whose polar surfaces are critical for interaction signaling pathway is preferentially activated by M-CSF with PU.1 (Ortiz et al., 1999). Tyrosine phosphorylation as compared the G-CSF signals during normal hema- of IRF-8 prevents it from directly binding DNA, but topoiesis. The finding that the MCSFR binds phospho- allows it to do so after interaction with other IRFs or lipase C-g via Y721 whereas such interaction has not PU.1 (Sharf et al., 1997). IRF-8 associates with IRF-1 or been described for the GCSFR supports this proposal IRF-2 to bind an interferon-stimulated response element (Bourette et al., 1997). Activated phospholipase C-g with two GAAANN half sites, and IRF-8:PU.1 com- releases diacylglycerol, which activates PKC. plexes bind an Ets/IRF composite element containing a Both c-Jun(À/À) and JunB(À/À) cells develop all the GGAA PU.1 site either preceded or followed by a single hematopoietic lineages in vivo, but as with the C/EBPs GAAANN element (Meraro et al., 2002; Tamura et al., redundancy might obscure a in these mice 2005). The SHP2 protein tyrosine phosphatase acts on (Eferl et al., 1999). Mice lacking JunB specifically in IRF-8 to prevent it from inducing the NF1 gene (Huang hematopoietic cells develop increased granulocytes et al., 2007b). SHP2 activity diminishes during myeloid (Passegue et al., 2001); this may represent loss of the differentiation, allowing increased IRF-8 activity and anti-proliferative effect of JunB rather than an effect on facilitating differentiation in cooperation with PU.1 lineage commitment. (Kautz et al., 2001; Kakar et al., 2005). In addition to Fos:Jun interactions, the MafB bZIP IRF-8(À/À) mice have reduced macrophages and transcription factor can zipper with c-Fos, and c-Maf increased granulocytes and form increased CFU-G at the canheterodimerizewithc-Jun,JunBorc-Fos,tobind expense of CFU-M in G-CSF, M-CSF or GM-CSF extended AP-1 sites with consensus 50-TGA(C/G)TCAG (Holtschke et al., 1996; Tsujimura et al., 2002). Introduction CA-30 (Kataoka et al., 1994). MafB is expressed exclu- of IRF-8 into IRF-8(À/À) marrow cells rescues monopoi- sively in monocyte/macrophage cells within hematopoiesis esis at the expense of granulopoiesis dependent on its PU.1 (Sieweke et al., 1996). Exogeneous MafB or c-Maf leads to interaction and DNA-binding domains (Tsujimura et al., monocytic development of myeloid cell lines (Hegde et al., 2002). Integrating these observations with the finding that 1999; Kelly et al., 2000). Downregulation of MafB is increased PU.1 levels are required for monopoiesis as required for myeloid maturation (Bakri et al., compared to granulopoiesis leads to the suggestion that 2005). MafB(À/À) fetal liver cells have normal numbers of higher levels of PU.1 facilitate interaction with IRF-8 to myeloid CFUs, but these immature cells are unable to give regulate genes required for monocyte lineage commitment rise to F4/80-expressing macrophages, suggesting a role for and maturation via Ets/IRF composite elements. MafB and perhaps MafB:Fos complexes late but not early in monocyte lineage development (Aziz et al., 2006; Moriguchi et al., 2006). AP-1 and interaction with Maf, PU.1 or C/EBP c-Jun directly interacts with and enhances the ability of PU.1 to activate the MCSFR and IL-1b promoters in the AP-1s, like the C/EBPs, are a subfamily of bZIP trans- absence of an AP-1 cis element, and PU.1 and c-Jun cription factors. Within the AP-1 family, Jun proteins cooperatively regulates the monocytic macrosialin and heterodimerize with c-Fos, FosB, Fra1 or Fra2 to bind scavenger receptor promoters via distinct binding sites

Oncogene Myeloid development AD Friedman 6820 (Moulton et al., 1994; Bassuk and Leiden, 1995; Li et al., we utilized LZs with eight acid (LZE) or eight basic 1998; Behre et al., 1999; Grondin et al., 2007). Interaction (LZK) residues in their salt bridge positions (O’Shea et al., of c-Jun homodimers with PU.1 depends on integrity of 1993). C/EBPaLZE:C/EBPaLZK preferentially binds a residues in the c-Jun BR and is augmented by contact of C/EBP site, c-JunLZE:c-FosLZK an AP-1 site and PU.1 with C/EBPb bound to DNA nearby (Grondin C/EBPaLZE:c-JunLZK a hybrid element. In murine et al., 2007). The C-terminalzinc finger of GATA-1 myeloid progenitors, C/EBPa:c-Jun or C/EBPa:c-Fos competes with the DNA-binding BR of c-Jun for LZE:LZK heterodimers induced monocyte as opposed interaction with the Ets domain of PU.1 (Zhang et al., to granulocyte lineage commitment with markedly 1999; Liew et al., 2006). This is a potentialmechanism to increased potency compared with C/EBPa homodimers prevent myeloid gene activation in erythroid cells. The or c-Jun:c-Fos heterodimers, demonstrating a positive C/EBPa LZ also competes with c-Jun for interaction functionalconsequence of C/EBP:AP-1 bZIP subfamily with PU.1 in the absence of DNA (Reddy et al., 2002), interaction (Cai et al., 2006). but when bound to DNA C/EBPa may in specific contexts, like C/EBPb, augment PU.1 activity as these factors cooperatively activate myeloid promoters (Oelgeschla¨ ger et al., 1996). c-Jun rescues monocytic NF-jB and interaction with C/EBP differentiation in PU.1-knockdown marrow cells (Steidl et al., 2006), but its effect in PU.1(À/À) cells has not been NF-kB is a key regulator of the inflammatory response evaluated. Also of note, c-Jun and JunB levels are in mature granulocytes and monocytes. There are five reduced in PU.1-knockdown HSCs, although PU.1 binds NF-kB family members, c-Rel, Rel A or p65, Rel B, NF- the JunB but not the c-Jun promoter (Steidl et al., 2006). kB1 or p50 and NF-kB2 or p52. Each has a 300 amino- c-Jun or c-Fos interacts with and prevents C/EBP acid Relhomologydomain that mediates dimerization, bZIP DNA-binding, even if the c-Fos or c-Jun BRs are DNA binding and trans-activation. p65 has a trans- deleted, suggesting direct interaction via their LZ activation domain, and p50 can repress transcription. domains (Hsu et al., 1994). Similarly, C/EBPa binds The p50:p65 heterodimer predominates in most cell c-Jun, but not if the LZ is deleted from either of these types. p52 partially substitutes for the lack of p50 and proteins, and c-Jun inhibits C/EBPa DNA-binding cRelfor the lack of p65 (Hoffmann et al., 2003). C/EBPb (Rangatia et al., 2002, 2003). These studies suggest, and NF-kB cooperatively bind and activate the IL-6, IL- but do not prove, direct zippering (hydrophobic surface 8, G-CSF, serum amyloid, intercellular adhesion mole- interaction) between c-Jun or c-Fos and C/EBPa or cule 1, dismutase and Mediterranean C/EBPb. Challenging this conclusion are the results promoters during the inflammatory response in myeloid obtained with a zipper peptide chip in which none of the and other cells (Dunn et al., 1994; Kunsch et al., 1994; AP-1 or Maf LZs interact with C/EBP LZs, though Xia et al., 1997; Maehara et al., 1999; Papin et al., 2003). Jun:Jun, Jun:Fos and MafB:Fos interactions are Co-immunoprecipitation demonstrates interaction of detected (Newman and Keating, 2003). A recent set of bacterially expressed C/EBPa or C/EBPb with bacte- experiments confirms C/EBP:AP-1 zippering. In a rially expressed or in vitro translated p50 or p65, zipper swap:gelshift assay, heterologous LZs were mapping to the bZIP domain of C/EBP and to the Rel substituted in place of the C/EBPa LZ in the full-length domain of p65 (Matsusaka et al., 1993; Stein protein. These were incubated with the C/EBPa bZIP et al., 1993). C/EBPa or C/EBPb cooperate with NF-kB domain and a radiolabeled C/EBP-binding site. Coiled- p50 to induce bcl-2 transcription and inhibit in coilLZ interaction positions the two C/EBP a BRs hematopoietic cells; the C/EBPa BR3 or R300G properly for DNA binding. C/EBPa or C/EBPb LZs variants, having four or one altered residues in the BR, zippered with the c-Jun, JunB and c-Fos but not the demonstrate reduced binding to p50 but not p65 and an c-Maf or MafB LZs. Also, co-immunoprecipitation inability to induce bcl-2 (Paz-Priel et al., 2005). This assay demonstrated that C/EBPa interacts with endo- study also found that endogenous C/EBPa preferentially genous or exogenous c-Jun, JunB or c-Fos but not if two interacts with endogenous p50 compared with p65 in leucines in the LZ are changed to valine. Interaction extracts from the HL-60 or myeloid cell lines. with the AP-1 proteins by co-immunoprecipitation was In contrast to wild-type C/EBPa, favoring monocytic weaker than with C/EBPb, perhaps explaining their lack lineage commitment, the C/EBPa BR3 variant favors of detection on the zipper chip (Cai et al., 2006). A granulopoiesis when expressed in myeloid progenitors scheme for predicting interaction strengths between LZs (Wang et al., 2006). The BR3 mutant also specifically enumerates contacts between acidic residues D or E and lacks the ability to inhibit phorbol ester-mediated basic residues R or K in the e and g salt bridge positions induction of JunB in the 32DPKCd cell line (Liu (Vinson et al., 1993). C/EBPa:C/EBPa, c-Fos:c-Jun or et al., 2003). These findings lead to the speculation that c-Fos:JunB has four, C/EBPa:c-Jun has two and C/EBPa and NF-kB p50 directly interact to coopera- C/EBPa:JunB or C/EBPa:c-Fos has three LZ salt tively induce a subset of genes in immature myeloid cells bridges. The relative weakness of C/EBP:AP-1 interac- required for monocyte development. Although myeloid tions suggests that gene activation via novelDNA defects have not been observed in p50(À/À) mice, other elements rather than cross-inhibition of binding to NF-kB family members may compensate (Sha et al., C/EBP and AP-1 sites will predominate in vivo.To 1995). In more mature myeloid cells, phosphorylation- evaluate activities of specific homodimers or heterodimers, dependent interaction of the N-terminalregion of

Oncogene Myeloid development AD Friedman 6821 C/EBPe with NF-kB p65 contributes to transcriptional encoding an inducer of monopoiesis, such as PU.1, with induction (Chumakov et al., 2007). PU.1 normally activating a repressor of terminal granulopoiesis (Laslo et al., 2006). Analysis of genes induced by high levels of PU.1 identified Egr proteins and Nab-2 as candidates for Retinoic acid and vitamin D receptors repressing granulopoiesis, while at the same time contributing to monopoiesis (Laslo et al., 2006). Egr-1 RARs bind 50-(A/G)G(G/T)TCAN (A/G)G(G/ 2À5 and Egr-2 are -finger transcription factors that bind T)TCA -30 via their zinc-finger domains as heterodimers the consensus 50-GCGGGGCG-30 and can activate or with RXR proteins (Naar et al., 1991; Umesono et al., repress transcription (Crosby et al., 1991). Egr-1 1991). RARs are widely expressed, with RARa prefer- stimulates monocyte differentiation in myeloid cell lines entially found in myeloid cells (de The et al., 1989). and murine marrow progenitors at the expense of Dominant inhibition of RARa arrests granulopoiesis granulopoiesis (Nguyen et al., 1993; Krishnaraju et al., at the stage (Tsai and Collins, 1993). 1995, 1998, 2001). Egr-1(À/À) mice develop normal RARa1(À/À)RARg(À/À) neutrophils do not proceed numbers of macrophages, as do Egr-2(À/À) fetalliver past the stage (Labrecque et al., 1998). Regu- cells; however, expression of a dominant-negative Egr lation of the C/EBPe promoter by RARa may account in protein or analysis of Egr-1(À/À);Egr-2( þ /À) marrow part for the role of RARs in granulopoiesis (Chih et al., cells uncovers defective monocytic maturation in 1997). RARs also activate the CD18 promoter in M-CSF but not in GM-CSF (Lee et al., 1996; Laslo maturing myeloid cells, in cooperation with the Ets et al., 2006). Gene activation by Egr-1 or Egr-2 family member GA-binding protein, and mediate their apparently stimulates monocytic maturation. Consistent cell cycle arrest (Bush et al., 2003; Walkley et al., 2004). with the idea that Egr:Nab-2 complexes repress granu- Retinoic acid increases the formation of CFU-G at the lopoiesis, Egr-2 or Nab-2 knockdown induce neutro- expense of CFU-M from marrow progenitors, and philic genes including Gfi-1 in a myeloid cell line, and 1a,25-dihydroxyvitamin D , which activates the related 3 Egr-2/Nab-2 represses the Gfi-1 promoter via an Egr- (VDR):RXR complex, increases binding site (Laslo et al., 2006). The same study found CFU-M at the expense of CFU-G (Douer and Koeffler, that Gfi-1 represses the Egr-2 promoter, providing 1982; Koeffler et al., 1984). When retinoic acid and cross-inhibition that stabilizes the neutrophil fate. vitamin D are added together, monocytic development is Gfi-1 also directly interacts with and represses induced, and VDR:RXR complexes bind and repress trans-activation by PU.1, providing an additional RAR:RXR-responsive elements, suggesting that - mechanism favoring granulopoiesis (Dahl et al., 2007). bound VDR drives monopoiesis by interacting with CAAT displacement protein (CDP) is a widely elements unaffected by RAR while inhibiting granulo- expressed protein that represses transcription by competi- poiesis via dominant inhibition of RAR-regulated genes tion with transactivators for sites which loosely resemble (Bastie et al., 2004). Downmodulation of RXRa, the a50-CCAAT-30 motif (Barberis et al., 1987; Luo and common partner of RAR and VDR, is induced by Skalnik 1996). Diminution of CDP DNA-binding G-CSF but not M-CSF and is required for terminal during granulocyte maturation and its ability to repress granulocytic but not monocytic maturation (Taschner the gp91-phox promoter suggests that downmodu- et al., 2007). How RAR and VDR activation and later lation of CDP is required for terminal neutrophil downregulation integrates with additional transcrip- differentiation (Skalnik et al., 1991). 32Dcl3 cells expres- tional controls to mediate myeloid lineage specification sing exogenous CDP do not express C/EBPe or remains to be further elucidated. secondary granule proteins in G-CSF (Lawson et al., 1998; Khanna-Gupta et al., 2001). Consistent with the need to downmodulate CDP for terminal granulopoiesis, Gfi-1, Egr-1, 2, CAAT displacement protein and HoxA10 mice transgenically expressing CDP from the MMTV repress terminal differentiation LTR develop a myeloproliferative disease with increased neutrophils infiltrating marrow and (Cadieux Gfi-1 binds DNA via a C-terminalzinc-finger domain et al., 2006). and represses transcription via its N-terminalSnail/GFi-1 HoxA10 is preferentially expressed in immature (SNAG) domain (Grimes et al., 1996; Zweidler-Mckay myeloid cells within hematopoiesis and exogenous et al., 1996). Gfi-1 is expressed in lymphoid and HoxA10 stimulates monopoiesis while blocking terminal granulocytic cells but not in the monocyte lineage granulopoiesis (Sauvageau et al., 1994; Lawrence et al., (Karsunky et al., 2002; Hock et al., 2003; Duan and 1995; Taghon et al., 2002). HoxA10 represses the Horwitz, 2003). Gfi-1(À/À)miceorapatientexpressinga gp91-phox and p67-phox promoters in immature mutant Gfi-1 display defects in neutrophil maturation myeloid cells dependent on the presence of the SHP2 subsequent to the promyelocyte stage; abnormal cells are tyrosine phosphatase, which acts directly on HoxA10 present that retain primary granules and ring-shaped to allow DNA-binding (Eklund et al., 2000; Lindsey nuclei, but lack secondary and tertiary granule proteins et al., 2007). In contrast, tyrosine phosphorylation and aberrantly express monocyte-restricted genes (Hock of HoxA9 potentiates its ability to bind and activate et al., 2003; Person et al., 2003). These observations these genes in maturing cells that have reduced SHP2 contribute to a modelin which Gfi-1 represses a gene (Bei et al., 2005).

Oncogene Myeloid development AD Friedman 6822 Summary and perspectives for the future prescribed time? What are the criticalgenetic or protein targets of elevated PU.1 that allow monocyte lineage Figure 1 provides a model of myeloid lineage develop- progression, and why are they insensitive to lower levels ment. PU.1 appears to specify the lymphoid-myeloid and of PU.1? Does VDR, AP-1 or C/EBPa:AP-1 complex, GATA-1 the erythroid- hematopoietic IRF-8, or Egr-1/Egr-2 contribute to monocyte lineage branches, with PU.1:GATA-1, and possibly PU.1:GA- specification or RAR to granulocyte specification and not TA-2, cross-inhibition maintaining commitment in either only lineage maturation, and do they do so in coopera- direction. C/EBPa then specifies the GMP stage. Cross- tion with, independent of or via induction of PU.1? What inhibition between C/EBPa and Pax5 or Notch may serve are the roles of transcriptional co-activators and co- to fix this commitment decision. Increased PU.1 activity and chromatin structure in myeloid develop- favors monocyte over granulocyte lineage commitment. ment? How does crosstalk with cell cycle pathways This increase may result from C/EBPa activation of the influence terminalmaturation? Does NF- kB, which is PU.1 gene or as a result of PU.1 interaction with c-Jun. activated in leukemic stem cells (Guzman et al., 2001), C/EBPa:c-Jun, C/EBPa:c-Fos or C/EBPa:NF-kB hetero- play a role in normal myeloid stem cells in cooperation dimers may induce PU.1 or a protein that cooperates with C/EBPa? Is commitment to granulopoiesis a default with PU.1 to favor monocytic commitment. Perhaps pathway that occurs when PU.1 is not induced suffi- MCSFR signals favor increased PU.1 activity via one of ciently, or are there positive inducers of this lineage that these mechanisms compared to GCSFR signals. RARs increase due to GCSFR signals. Candidates for the latter contribute to granulocytic commitment and the VDR to include STAT3 (de Koning et al., 1996; Shimozaki et al., monocytic commitment. PU.1 induction of Egr-1 or Egr- 1997) and Id1-regulated basic helix-loop-helix proteins 2 facilitates maturation along the monocyte lineage, while (Leeanansaksiri et al., 2005; Jankovic et al., 2007). The C/EBPa induction of C/EBPe and perhaps Gfi-1 enables answers to these questions will provide important lessons granulocytic maturation. Downmodulation of SHP2 in , insights into myeloid transfor- activates IRF-8 while inactivating HoxA10 to contribute mation that will guide therapies aimed at inducing to monocytic and granulocytic maturation. MafB facil- differentiation, and tools for expanding normal myeloid itates late monocyte and loss of CDP late granulocyte cells from hematopoietic or even embryonic stem cells. development. Cross-inhibition between Gfi-1 and Egr/ Nab-2 maintains myeloid lineage fidelity. Acknowledgements Many questions remain. Are increased PU.1 levels required only at a critical developmental stage to specify AF is supported by the NationalInstitutes of Health,the monocytic commitment? What cytokine signals and SamuelWaxman Cancer Research Foundation, and the transcription factors cooperate to elevate PU.1 at the Children’s Cancer Foundation.

Mega, Eryth

MEP AP-1 VDR, IRF-8, MafB CFU-M Mono ?NFκB Egr-1,2 C/EBPα GATA-1 PU.1 HSC GMP C/EBPα PU.1 ?other PU.1 CDP, C/EBPα Gfi-1 HoxA10 LMP CFU-G Gran RAR, C/EBPε

CLP B,T Pax5, Notch,... Figure 1 A model for the transcriptional regulation of granulocyte and monocyte lineage commitment and maturation. Under the influence of GATA-binding protein 1 (GATA-1), the hematopoietic stem cell (HSC) differentiates into the megakaryocyte-erythroid progenitor (MEP). PU.1 directs the HSC to develop into a lymphoid-myeloid progenitor (LMP), which then further commits to the common lymphoid progenitor (CLP) branch or, directed by CCAAT/enhancer-binding protein alpha (C/EBPa), to the granulocyte- monocyte progenitor (GMP) branch. Cross-inhibition between GATA-1 and PU.1 serves to maintain HSC developmental fates, and similar cross-inhibition between C/EBPa and lymphoid regulators such as Pax5 and Notch may maintain CLP developmental decisions. Increased PU.1 activity directs the GMP to further commit to the monocytic lineage. C/EBPa induction of PU.1 transcription helps elevate PU.1 activity as does PU.1 interaction with c-Jun. AP-1 and NF-kB proteins may also have a role at this stage of hematopoiesis via direct interaction with C/EBPa, either contributing to PU.1 induction or activating a parallel pathway. C/EBPa and PU.1, at reduced levels, are also required for granulopoiesis, but another factor, perhaps a protein regulated by Id1, may be essentialfor commitment to the granulocytelineage.VDR, IRF-8, MafB, Egr-1 and Egr-2 direct monocytic maturation, and RARs and C/EBPe act similarly during terminal granulocytic development. Loss of CDP- and HoxA10-repressive activities and onset of Gfi-1-mediated repression contributes granulopoiesis. Cross-inhibition between Gfi-1 and Egr-1,2/Nab2 co-repressor complexes maintains GMP developmental decisions.

Oncogene Myeloid development AD Friedman 6823 References

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