SALL4

SALL4 contains one zinc finger in its amino (N-) terminus and three clusters of zinc fingers that each coordinates zinc with two cysteines and two histidines (Cys₂His₂-type) that potentially confer nucleic acid binding activity. SALL4B lacks two of the zinc finger clusters found in the A isoform. Although it remains unclear which zinc finger cluster is responsible for SALL4’s DNA binding property

Different SALL family members can form hetero- or homodimers via their conserved glutamine (Q)-rich region.{{cite journal | vauthors = Sweetman D, Smith T, Farrell ER, Chantry A, Munsterberg A | title = The conserved glutamine-rich region of chick csal1 and csal3 mediates protein interactions with other spalt family members. Implications for Townes-Brocks syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 8 | pages = 6560–6566 | date = Feb 2003 | pmid = 12482848 | doi = 10.1074/jbc.M209066200 | s2cid = 45225368 | doi-access = free }} SALL4 has at least one canonical nuclear localization signal (NLS) with the K-K/R-X-K/R motif in the N-terminal portion of the protein shared among both A and B isoforms (residues 64–67).{{cite journal | vauthors = Wu M, Yang F, Ren Z, Jiang Y, Ma Y, Chen Y, Dai W | title = Identification of the nuclear localization signal of SALL4B, a stem cell transcription factor | journal = Cell Cycle | volume = 13 | issue = 9 | pages = 1456–1462 | date = 2014 | pmid = 24626181 | doi = 10.4161/cc.28418 | pmc=4050143}} One report has suggested that with a mutated NLS sequence, SALL4 cannot localize to the nucleus. Through a 12-amino acid sequence in its N-terminus (N-12a.a.), SALL4 binds to retinoblastoma binding protein 4 (RBBP4), a subunit of the nucleosome remodeling and histone deacetylation (NuRD) complex, which also contains chromodomain-helicase-DNA binding proteins (CHD3/4 or Mi-2a/b), metastasis-associated proteins (MTA), methyl-CpG-binding domain proteins (MBD2 or MBD3), and histone deacetylases (HDAC1 and HDAC2).{{cite journal | vauthors = Gao C, Dimitrov T, Yong KJ, Tatetsu H, Jeong HW, Luo HR, Bradner JE, Tenen DG, Chai L | title = Targeting transcription factor SALL4 in acute myeloid leukemia by interrupting its interaction with an epigenetic complex | journal = Blood | volume = 121 | issue = 8 | pages = 1413–1421 | date = Feb 2013 | pmid = 23287862 | doi = 10.1182/blood-2012-04-424275 | pmc=3578956}}{{cite journal | vauthors = Hong W, Nakazawa M, Chen YY, Kori R, Vakoc CR, Rakowski C, Blobel GA | title = FOG-1 recruits the NuRD repressor complex to mediate transcriptional repression by GATA-1 | journal = The EMBO Journal | volume = 24 | issue = 13 | pages = 2367–2378 | date = Jul 2005 | pmid = 15920470 | doi = 10.1038/sj.emboj.7600703 | pmc=1173144}}{{cite journal | vauthors = Lauberth SM, Rauchman M | title = A conserved 12-amino acid motif in Sall1 recruits the nucleosome remodeling and deacetylase corepressor complex | journal = The Journal of Biological Chemistry | volume = 281 | issue = 33 | pages = 23922–23931 | date = Aug 2006 | pmid = 16707490 | doi = 10.1074/jbc.M513461200 | s2cid = 22060389 | url = https://escholarship.org/uc/item/15q6p0q9 | doi-access = free }}{{cite journal | vauthors = Lu J, Jeong HW, Jeong H, Kong N, Yang Y, Carroll J, Luo HR, Silberstein LE, Chai L | title = Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5577 | date = 2009 | pmid = 19440552 | doi = 10.1371/journal.pone.0005577 | pmc=2679146| bibcode = 2009PLoSO...4.5577L | doi-access = free }} This association allows SALL4 to act as a transcriptional repressor. Accordingly, SALL4 has been shown to localize to heterochromatin regions in cells, for which its last zinc finger cluster (shared between SALL4A and B) is necessary.{{cite journal | vauthors = Sakaki-Yumoto M, Kobayashi C, Sato A, Fujimura S, Matsumoto Y, Takasato M, Kodama T, Aburatani H, Asashima M, Yoshida N, Nishinakamura R | title = The murine homolog of SALL4, a causative gene in Okihiro syndrome, is essential for embryonic stem cell proliferation, and cooperates with Sall1 in anorectal, heart, brain and kidney development | journal = Development | volume = 133 | issue = 15 | pages = 3005–3013 | date = Aug 2006 | pmid = 16790473 | doi = 10.1242/dev.02457 | s2cid = 16264471 | doi-access = }} Beside the NuRD complex, SALL4 is reportedly able to bind to other epigenetic modifiers such as histone lysine-specific demethylase 1 (LSD1), which is frequently associated with the NuRD complex and subsequently gene repression.{{cite journal | vauthors = Liu L, Souto J, Liao W, Jiang Y, Li Y, Nishinakamura R, Huang S, Rosengart T, Yang VW, Schuster M, Ma Y, Yang J | title = Histone lysine-specific demethylase 1 (LSD1) protein is involved in Sal-like protein 4 (SALL4)-mediated transcriptional repression in hematopoietic stem cells | journal = The Journal of Biological Chemistry | volume = 288 | issue = 48 | pages = 34719–34728 | date = Nov 2013 | pmid = 24163373 | doi = 10.1074/jbc.M113.506568 | pmc=3843083| doi-access = free }} In addition, SALL4 can also activate gene expression via the recruitment of the mixed lineage leukemia (MLL) protein, which is a homolog of Drosophila Trithorax and yeast Set1 proteins and has histone 3 lysine 4 (H3K4) trimethylation activity.{{cite journal | vauthors = Li A, Yang Y, Gao C, Lu J, Jeong HW, Liu BH, Tang P, Yao X, Neuberg D, Huang G, Tenen DG, Chai L | title = A SALL4/MLL/HOXA9 pathway in murine and human myeloid leukemogenesis | journal = The Journal of Clinical Investigation | volume = 123 | issue = 10 | pages = 4195–4207 | date = Oct 2013 | pmid = 24051379 | doi = 10.1172/JCI62891 | pmc=3784519}} This interaction is best characterized in the co-regulation of HOXA9 gene by SALL4 and MLL in leukemic cells.

In mouse ESCs, Sall4 was found to bind the essential stem cell factor, octamer-binding transcription factor 4 (Oct4), in two separate unbiased mass spectrometry (spec) screens{{cite journal | vauthors = van den Berg DL, Snoek T, Mullin NP, Yates A, Bezstarosti K, Demmers J, Chambers I, Poot RA | title = An Oct4-centered protein interaction network in embryonic stem cells | journal = Cell Stem Cell | volume = 6 | issue = 4 | pages = 369–381 | date = Apr 2010 | pmid = 20362541 | doi = 10.1016/j.stem.2010.02.014 | pmc=2860243}}{{cite journal | vauthors = Pardo M, Lang B, Yu L, Prosser H, Bradley A, Babu MM, Choudhary J | title = An expanded Oct4 interaction network: implications for stem cell biology, development, and disease | journal = Cell Stem Cell | volume = 6 | issue = 4 | pages = 382–395 | year = 2010 | pmid = 20362542 | pmc = 2860244 | doi = 10.1016/j.stem.2010.03.004 }} Sall4 can also bind other important pluripotency proteins such as Nanog and sex determining region Y (SRY)-box 2 protein (Sox2).{{cite journal | vauthors = Wu Q, Chen X, Zhang J, Loh YH, Low TY, Zhang W, Zhang W, Sze SK, Lim B, Ng HH | title = Sall4 interacts with Nanog and co-occupies Nanog genomic sites in embryonic stem cells | journal = The Journal of Biological Chemistry | volume = 281 | issue = 34 | pages = 24090–24094 | date = Aug 2006 | pmid = 16840789 | doi = 10.1074/jbc.C600122200 | s2cid = 46337274 | doi-access = free }}{{cite journal | vauthors = Tanimura N, Saito M, Ebisuya M, Nishida E, Ishikawa F | title = Stemness-related factor Sall4 interacts with transcription factors Oct-3/4 and Sox2 and occupies Oct-Sox elements in mouse embryonic stem cells | journal = The Journal of Biological Chemistry | volume = 288 | issue = 7 | pages = 5027–5038 | date = Feb 2013 | pmid = 23269686 | doi = 10.1074/jbc.M112.411173 | pmc=3576104| doi-access = free }} Together these proteins can affect each other’s expression patterns as well as their own, thus forming a mESC-specific transcriptional regulatory circuit.{{cite journal | vauthors = Kim J, Chu J, Shen X, Wang J, Orkin SH | title = An extended transcriptional network for pluripotency of embryonic stem cells | journal = Cell | volume = 132 | issue = 6 | pages = 1049–1061 | date = Mar 2008 | pmid = 18358816 | doi = 10.1016/j.cell.2008.02.039 | pmc=3837340}} SALL4 has also been reported to bind T-box 5 protein (Tbx5) in cardiac tissues as well as genetically interact with Tbx5 in mouse limb development.{{cite journal | vauthors = Koshiba-Takeuchi K, Takeuchi JK, Arruda EP, Kathiriya IS, Mo R, Hui CC, Srivastava D, Bruneau BG | title = Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart | journal = Nature Genetics | volume = 38 | issue = 2 | pages = 175–183 | date = Feb 2006 | pmid = 16380715 | doi = 10.1038/ng1707 | s2cid = 30899786 }} Other binding partners of SALL4 include promyelocytic leukemia zinc finger protein (PLZF) in sperm precursor cells,{{cite journal | vauthors = Hobbs RM, Fagoonee S, Papa A, Webster K, Altruda F, Nishinakamura R, Chai L, Pandolfi PP | title = Functional antagonism between Sall4 and Plzf defines germline progenitors | journal = Cell Stem Cell | volume = 10 | issue = 3 | pages = 284–298 | date = Mar 2012 | pmid = 22385656 | doi = 10.1016/j.stem.2012.02.004 | pmc=3299297}} Rad50 during DNA damage repair,{{cite journal | vauthors = Xiong J, Todorova D, Su NY, Kim J, Lee PJ, Shen Z, Briggs SP, Xu Y | title = Stemness factor Sall4 is required for DNA damage response in embryonic stem cells | journal = The Journal of Cell Biology | volume = 208 | issue = 5 | pages = 513–520 | date = Mar 2015 | pmid = 25733712 | doi = 10.1083/jcb.201408106 | pmc=4347641}} and b-catenin downstream of the Wnt signaling pathway. Since most of these interactions were identified by mass-spec or co-immunoprecipitation, whether they are direct are unknown. Through chromatin immunoprecipitation (ChIP) followed by next-generation sequencing or microarray, some SALL4 targets have been identified.{{cite journal | vauthors = Yang J, Chai L, Gao C, Fowles TC, Alipio Z, Dang H, Xu D, Fink LM, Ward DC, Ma Y | title = SALL4 is a key regulator of survival and apoptosis in human leukemic cells | journal = Blood | volume = 112 | issue = 3 | pages = 805–813 | date = Aug 2008 | pmid = 18487508 | doi = 10.1182/blood-2007-11-126326 | pmc=2481537}} A key verified target gene encodes the enzyme phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN). PTEN is a tumor suppressor that keeps uncontrolled cell growth in check through inducing programmed cell death, or apoptosis. SALL4 binds the PTEN promoter and recruits the NuRD complex to mediate its repression, thus leads to proliferation of cells.

In mouse embryos, SALL4 expression is detectable as early as the two-cell stage. Its expression persists through 8- and 16-cell stages to the blastocyst, where it is found in some cells of the trophectoderm and inner cell mass (ICM), from which mouse ESCs are derived.{{cite journal | vauthors = Elling U, Klasen C, Eisenberger T, Anlag K, Treier M | title = Murine inner cell mass-derived lineages depend on Sall4 function | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 44 | pages = 16319–16324 | date = Oct 2006 | pmid = 17060609 | doi = 10.1073/pnas.0607884103 | pmc=1637580| bibcode = 2006PNAS..10316319E | doi-access = free }} SALL4 is an important factor for maintaining the “stemness” of ESCs of both mouse and human origin, since loss of Sall4 leads to differentiation of these pluripotent cells down the trophectoderm lineage.{{cite journal | vauthors = Zhang J, Tam WL, Tong GQ, Wu Q, Chan HY, Soh BS, Lou Y, Yang J, Ma Y, Chai L, Ng HH, Lufkin T, Robson P, Lim B | title = Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1 | journal = Nature Cell Biology | volume = 8 | issue = 10 | pages = 1114–1123 | date = Oct 2006 | pmid = 16980957 | doi = 10.1038/ncb1481 | s2cid = 37507421 }} This is possibly due to down-regulation of Pou5f1 (encoding Oct4) expression and up-regulation of caudal-type homeobox 2 (Cdx2) gene expression. Sall4 is part of the transcriptional regulatory network that includes other pluripotent factors such as Oct4, Nanog, and Sox2{{cite journal | vauthors = Wang J, Rao S, Chu J, Shen X, Levasseur DN, Theunissen TW, Orkin SH | title = A protein interaction network for pluripotency of embryonic stem cells | journal = Nature | volume = 444 | issue = 7117 | pages = 364–368 | date = Nov 2006 | pmid = 17093407 | doi = 10.1038/nature05284 | bibcode = 2006Natur.444..364W | s2cid = 4404796 }}{{cite journal | vauthors = Zhou Q, Chipperfield H, Melton DA, Wong WH | title = A gene regulatory network in mouse embryonic stem cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 42 | pages = 16438–16443 | date = Oct 2007 | pmid = 17940043 | doi = 10.1073/pnas.0701014104 | pmc=2034259| bibcode = 2007PNAS..10416438Z | doi-access = free }} Because of its important role in early development, genetically mutated mice without functioning SALL4 die early on at the peri-implantation stage, while heterozygous mice have neural, kidney, heart defects and limb abnormalities.{{cite journal | vauthors = Warren M, Wang W, Spiden S, Chen-Murchie D, Tannahill D, Steel KP, Bradley A | title = A Sall4 mutant mouse model useful for studying the role of Sall4 in early embryonic development and organogenesis | journal = Genesis | volume = 45 | issue = 1 | pages = 51–58 | date = Jan 2007 | pmid = 17216607 | doi = 10.1002/dvg.20264 | pmc=2593393}}

The various SALL4-null mouse models mimic human mutations in the SALL4 gene, which were shown to cause developmental problems in patients with Okihiro/Duane-Radial-ray syndrome.{{cite journal | vauthors = Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W | title = Okihiro syndrome is caused by SALL4 mutations | journal = Human Molecular Genetics | volume = 11 | issue = 23 | pages = 2979–2987 | date = Nov 2002 | pmid = 12393809 | doi = 10.1093/hmg/11.23.2979| doi-access = free }}{{cite journal | vauthors = Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC | title = Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family | journal = American Journal of Human Genetics | volume = 71 | issue = 5 | pages = 1195–1199 | date = Nov 2002 | pmid = 12395297 | doi = 10.1086/343821 | pmc=385096}} These individuals frequently have family history of hand malformation and eye movement disorders.

SALL4 expression is low to undetectable in most adult tissues with the exception of germ cells and human blood progenitor cells.{{cite journal | vauthors = Gao C, Kong NR, Li A, Tatetu H, Ueno S, Yang Y, He J, Yang J, Ma Y, Kao GS, Tenen DG, Chai L | title = SALL4 is a key transcription regulator in normal human hematopoiesis | journal = Transfusion | volume = 53 | issue = 5 | pages = 1037–1049 | date = May 2013 | pmid = 22934838 | doi = 10.1111/j.1537-2995.2012.03888.x | pmc=3653586}} However, SALL4 is re-activated and mis-regulated in various cancers{{cite journal | vauthors = Miettinen M, Wang Z, McCue PA, Sarlomo-Rikala M, Rys J, Biernat W, Lasota J, Lee YS | title = SALL4 expression in germ cell and non-germ cell tumors: a systematic immunohistochemical study of 3215 cases | journal = The American Journal of Surgical Pathology | volume = 38 | issue = 3 | pages = 410–420 | date = Mar 2014 | pmid = 24525512 | doi = 10.1097/PAS.0000000000000116 | pmc=4041084}}{{cite journal | vauthors = Zhang X, Yuan X, Zhu W, Qian H, Xu W | title = SALL4: an emerging cancer biomarker and target | journal = Cancer Letters | volume = 357 | issue = 1 | pages = 55–62 | date = Feb 2015 | pmid = 25444934 | doi = 10.1016/j.canlet.2014.11.037 }} such as acute myeloid leukemia (AML),{{cite journal | vauthors = Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L | title = SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice | journal = Blood | volume = 108 | issue = 8 | pages = 2726–2735 | date = Oct 2006 | pmid = 16763212 | doi = 10.1182/blood-2006-02-001594 | pmc=1895586}} B-cell acute lymphocytic leukemia (B-ALL),{{cite journal | vauthors = Ueno S, Lu J, He J, Li A, Zhang X, Ritz J, Silberstein LE, Chai L | title = Aberrant expression of SALL4 in acute B cell lymphoblastic leukemia: mechanism, function, and implication for a potential novel therapeutic target | journal = Experimental Hematology | volume = 42 | issue = 4 | pages = 307–316.e8 | date = Apr 2014 | pmid = 24463278 | doi = 10.1016/j.exphem.2014.01.005 | pmc=4135469}} germ cell tumors,{{cite journal | vauthors = Cao D, Li J, Guo CC, Allan RW, Humphrey PA | title = SALL4 is a novel diagnostic marker for testicular germ cell tumors | journal = The American Journal of Surgical Pathology | volume = 33 | issue = 7 | pages = 1065–1077 | date = Jul 2009 | pmid = 19390421 | doi = 10.1097/PAS.0b013e3181a13eef | s2cid = 26881393 }} gastric cancer,{{cite journal | vauthors = Zhang L, Xu Z, Xu X, Zhang B, Wu H, Wang M, Zhang X, Yang T, Cai J, Yan Y, Mao F, Zhu W, Shao Q, Qian H, Xu W | title = SALL4, a novel marker for human gastric carcinogenesis and metastasis | journal = Oncogene | volume = 33 | issue = 48 | pages = 5491–5500 | date = Nov 2014 | pmid = 24276240 | doi = 10.1038/onc.2013.495 | s2cid = 9201315 | doi-access = free }} breast cancer,{{cite journal | vauthors = Kobayashi D, Kuribayshi K, Tanaka M, Watanabe N | title = SALL4 is essential for cancer cell proliferation and is overexpressed at early clinical stages in breast cancer | journal = International Journal of Oncology | volume = 38 | issue = 4 | pages = 933–939 | date = Apr 2011 | pmid = 21274508 | doi = 10.3892/ijo.2011.929 | doi-access = free }} hepatocellular carcinoma (HCC),{{cite journal | vauthors = Yong KJ, Gao C, Lim JS, Yan B, Yang H, Dimitrov T, Kawasaki A, Ong CW, Wong KF, Lee S, Ravikumar S, Srivastava S, Tian X, Poon RT, Fan ST, Luk JM, Dan YY, Salto-Tellez M, Chai L, Tenen DG | title = Oncofetal gene SALL4 in aggressive hepatocellular carcinoma | journal = The New England Journal of Medicine | volume = 368 | issue = 24 | pages = 2266–2276 | date = Jun 2013 | pmid = 23758232 | doi = 10.1056/NEJMoa1300297 | pmc=3781214}}{{cite journal | vauthors = Oikawa T, Kamiya A, Zeniya M, Chikada H, Hyuck AD, Yamazaki Y, Wauthier E, Tajiri H, Miller LD, Wang XW, Reid LM, Nakauchi H | title = Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers | journal = Hepatology | volume = 57 | issue = 4 | pages = 1469–1483 | date = Apr 2013 | pmid = 23175232 | pmc = 6669886 | doi = 10.1002/hep.26159 }} lung cancer,{{cite journal | vauthors = Morita S, Yoshida A, Goto A, Ota S, Tsuta K, Yokozawa K, Asamura H, Nakajima J, Takai D, Mori M, Oka T, Tamaru J, Itoyama S, Furuta K, Fukayama M, Tsuda H | title = High-grade lung adenocarcinoma with fetal lung-like morphology: clinicopathologic, immunohistochemical, and molecular analyses of 17 cases | journal = The American Journal of Surgical Pathology | volume = 37 | issue = 6 | pages = 924–932 | date = Jun 2013 | pmid = 23629442 | doi = 10.1097/PAS.0b013e31827e1e83 | s2cid = 22710166 }} and glioma.{{cite journal | vauthors = Zhang L, Yan Y, Jiang Y, Cui Y, Zou Y, Qian J, Luo C, Lu Y, Wu X | title = The expression of SALL4 in patients with gliomas: high level of SALL4 expression is correlated with poor outcome | journal = Journal of Neuro-Oncology | volume = 121 | issue = 2 | pages = 261–268 | date = Jan 2015 | pmid = 25359397 | doi = 10.1007/s11060-014-1646-4 | s2cid = 22232165 }} In many of these cancers, SALL4 expression was compared in tumor cells to the normal tissue counterpart, e.g. it is expressed in nearly half of primary human endometrial cancer samples, but not in normal or hyperplastic endometrial tissue samples.{{cite journal | vauthors = Li A, Jiao Y, Yong KJ, Wang F, Gao C, Yan B, Srivastava S, Lim GS, Tang P, Yang H, Tenen DG, Chai L | title = SALL4 is a new target in endometrial cancer | journal = Oncogene | volume = 34 | issue = 1 | pages = 63–72 | date = Jan 2015 | pmid = 24336327 | doi = 10.1038/onc.2013.529 | pmc=4059794}} Often, SALL4 expression is correlated with worse survival and poor prognosis such as in HCC, or with metastasis such as in endometrial cancer, colorectal carcinoma,{{cite journal | vauthors = Forghanifard MM, Moghbeli M, Raeisossadati R, Tavassoli A, Mallak AJ, Boroumand-Noughabi S, Abbaszadegan MR | title = Role of SALL4 in the progression and metastasis of colorectal cancer | journal = Journal of Biomedical Science | volume = 20 | pages = 6 | date = Jan 2013 | pmid = 23363002 | doi = 10.1186/1423-0127-20-6 | pmc=3599462 | issue=1 | doi-access = free }} and esophageal squamous cell carcinoma.{{cite journal | vauthors = Forghanifard MM, Ardalan Khales S, Javdani-Mallak A, Rad A, Farshchian M, Abbaszadegan MR | title = Stemness state regulators SALL4 and SOX2 are involved in progression and invasiveness of esophageal squamous cell carcinoma | journal = Medical Oncology | volume = 31 | issue = 4 | pages = 922 | date = Apr 2014 | pmid = 24659265 | doi = 10.1007/s12032-014-0922-7 | s2cid = 207374970 }} It is unclear how SALL4 expression is de-regulated in malignant cells, but DNA hypomethylation in its intron 1 region has been observed in B-ALL.

In breast cancer, Signal transducer and activator of transcription 3 (STAT3) has been reported to directly activate SALL4 expression.{{cite journal | vauthors = Bard JD, Gelebart P, Amin HM, Young LC, Ma Y, Lai R | title = Signal transducer and activator of transcription 3 is a transcriptional factor regulating the gene expression of SALL4 | journal = FASEB Journal | volume = 23 | issue = 5 | pages = 1405–1414 | date = May 2009 | pmid = 19151334 | doi = 10.1096/fj.08-117721 | doi-access = free | s2cid = 20179918 }} Furthermore, canonical Wnt signaling has been proposed to activate SALL4 gene expression in both development{{cite journal | vauthors = Young JJ, Kjolby RA, Kong NR, Monica SD, Harland RM | title = Spalt-like 4 promotes posterior neural fates via repression of pou5f3 family members in Xenopus | journal = Development | volume = 141 | issue = 8 | pages = 1683–1693 | date = Apr 2014 | pmid = 24715458 | doi = 10.1242/dev.099374 | pmc=3978834}}{{cite journal | vauthors = Böhm J, Sustmann C, Wilhelm C, Kohlhase J | title = SALL4 is directly activated by TCF/LEF in the canonical Wnt signaling pathway | journal = Biochemical and Biophysical Research Communications | volume = 348 | issue = 3 | pages = 898–907 | date = Sep 2006 | pmid = 16899215 | doi = 10.1016/j.bbrc.2006.07.124 }} and in cancer. In leukemia, the mechanism of SALL4 function is better characterized; mice with over-expression of human SALL4 develop myelodysplatic syndromes (MDS)-like symptoms and eventually AML. This is consistent with high level of SALL4 expression correlating with high-risk MDS patients.{{cite journal | vauthors = Shuai X, Zhou D, Shen T, Wu Y, Zhang J, Wang X, Li Q | title = Overexpression of the novel oncogene SALL4 and activation of the Wnt/beta-catenin pathway in myelodysplastic syndromes | journal = Cancer Genetics and Cytogenetics | volume = 194 | issue = 2 | pages = 119–124 | date = Oct 2009 | pmid = 19781444 | doi = 10.1016/j.cancergencyto.2009.06.006 }}{{cite journal | vauthors = Wang F, Guo Y, Chen Q, Yang Z, Ning N, Zhang Y, Xu Y, Xu X, Tong C, Chai L, Cui W | title = Stem cell factor SALL4, a potential prognostic marker for myelodysplastic syndromes | journal = Journal of Hematology & Oncology | volume = 6 | issue = 1 | pages = 73 | date = Sep 2013 | pmid = 24283704 | doi = 10.1186/1756-8722-6-73 | pmc=3856454 | doi-access = free }} Further elucidating its tumorigenesis function, knocking down SALL4 expression with short hairpin-RNA in leukemic cells or treating these cells with a peptide that mimics the N-12aa of SALL4 to inhibit its interaction with the NuRD complex both result in cell death. These suggest the primary cancer-maintaining property of SALL4 is mediated through its transcriptional repressing function. These observations have led to growing interest in SALL4 as both a diagnostic tool as well as target in cancer therapy. For example, in solid tumors such as germ cell tumors, SALL4 protein expression has become a standard diagnostic biomarker.{{cite journal | vauthors = Ulbright TM, Tickoo SK, Berney DM, Srigley JR | title = Best practices recommendations in the application of immunohistochemistry in testicular tumors: report from the International Society of Urological Pathology consensus conference | journal = The American Journal of Surgical Pathology | volume = 38 | issue = 8 | pages = e50–9 | date = Aug 2014 | pmid = 24832161 | doi = 10.1097/PAS.0000000000000233 | s2cid = 11759077 }}

{{Academic-written review|Q=Q28273464}}

{{Reflist|33em}}

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• {{cite journal | vauthors = Sweetman D, Münsterberg A | title = The vertebrate spalt genes in development and disease | journal = Developmental Biology | volume = 293 | issue = 2 | pages = 285–293 | date = May 2006 | pmid = 16545361 | doi = 10.1016/j.ydbio.2006.02.009 | s2cid = 45268563 | url = https://ueaeprints.uea.ac.uk/id/eprint/1181/1/06_Sweetman_DevBiol_review.pdf }}
• {{cite journal | vauthors = Kohlhase J, Heinrich M, Schubert L, Liebers M, Kispert A, Laccone F, Turnpenny P, Winter RM, Reardon W | title = Okihiro syndrome is caused by SALL4 mutations | journal = Human Molecular Genetics | volume = 11 | issue = 23 | pages = 2979–2987 | date = Nov 2002 | pmid = 12393809 | doi = 10.1093/hmg/11.23.2979 | doi-access = free }}
• {{cite journal | vauthors = Al-Baradie R, Yamada K, St Hilaire C, Chan WM, Andrews C, McIntosh N, Nakano M, Martonyi EJ, Raymond WR, Okumura S, Okihiro MM, Engle EC | title = Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family | journal = American Journal of Human Genetics | volume = 71 | issue = 5 | pages = 1195–1199 | date = Nov 2002 | pmid = 12395297 | pmc = 385096 | doi = 10.1086/343821 }}
• {{cite journal | vauthors = Kohlhase J, Schubert L, Liebers M, Rauch A, Becker K, Mohammed SN, Newbury-Ecob R, Reardon W | title = Mutations at the SALL4 locus on chromosome 20 result in a range of clinically overlapping phenotypes, including Okihiro syndrome, Holt-Oram syndrome, acro-renal-ocular syndrome, and patients previously reported to represent thalidomide embryopathy | journal = Journal of Medical Genetics | volume = 40 | issue = 7 | pages = 473–478 | date = Jul 2003 | pmid = 12843316 | pmc = 1735528 | doi = 10.1136/jmg.40.7.473 }}
• {{cite journal | vauthors = Borozdin W, Wright MJ, Hennekam RC, Hannibal MC, Crow YJ, Neumann TE, Kohlhase J | title = Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum | journal = Journal of Medical Genetics | volume = 41 | issue = 8 | pages = e102 | date = Aug 2004 | pmid = 15286162 | pmc = 1735876 | doi = 10.1136/jmg.2004.019505 }}
• {{cite journal | vauthors = Kohlhase J, Holmes LB | title = Mutations in SALL4 in malformed father and daughter postulated previously due to reflect mutagenesis by thalidomide | journal = Birth Defects Research. Part A, Clinical and Molecular Teratology | volume = 70 | issue = 8 | pages = 550–551 | date = Aug 2004 | pmid = 15329836 | doi = 10.1002/bdra.20050 }}
• {{cite journal | vauthors = Borozdin W, Boehm D, Leipoldt M, Wilhelm C, Reardon W, Clayton-Smith J, Becker K, Mühlendyck H, Winter R, Giray O, Silan F, Kohlhase J | title = SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism | journal = Journal of Medical Genetics | volume = 41 | issue = 9 | pages = e113 | date = Sep 2004 | pmid = 15342710 | pmc = 1735888 | doi = 10.1136/jmg.2004.019901 }}
• {{cite journal | vauthors = Wabbels BK, Lorenz B, Kohlhase J | title = No evidence of SALL4-mutations in isolated sporadic duane retraction "syndrome" (DURS) | journal = American Journal of Medical Genetics Part A | volume = 131 | issue = 2 | pages = 216–218 | date = Dec 2004 | pmid = 15386473 | doi = 10.1002/ajmg.a.30321 | s2cid = 35230437 }}
• {{cite journal | vauthors = Kohlhase J, Chitayat D, Kotzot D, Ceylaner S, Froster UG, Fuchs S, Montgomery T, Rösler B | title = SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders | journal = Human Mutation | volume = 26 | issue = 3 | pages = 176–183 | date = Sep 2005 | pmid = 16086360 | doi = 10.1002/humu.20215 | s2cid = 32696827 | doi-access = free }}
• {{cite journal | vauthors = Miertus J, Borozdin W, Frecer V, Tonini G, Bertok S, Amoroso A, Miertus S, Kohlhase J | title = A SALL4 zinc finger missense mutation predicted to result in increased DNA binding affinity is associated with cranial midline defects and mild features of Okihiro syndrome | journal = Human Genetics | volume = 119 | issue = 1–2 | pages = 154–161 | date = Mar 2006 | pmid = 16402211 | doi = 10.1007/s00439-005-0124-7 | s2cid = 39709020 }}
• {{cite journal | vauthors = Terhal P, Rösler B, Kohlhase J | title = A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation | journal = American Journal of Medical Genetics Part A | volume = 140 | issue = 3 | pages = 222–226 | date = Feb 2006 | pmid = 16411190 | doi = 10.1002/ajmg.a.31060 | s2cid = 27878708 }}
• {{cite journal | vauthors = Ma Y, Cui W, Yang J, Qu J, Di C, Amin HM, Lai R, Ritz J, Krause DS, Chai L | title = SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice | journal = Blood | volume = 108 | issue = 8 | pages = 2726–2735 | date = Oct 2006 | pmid = 16763212 | pmc = 1895586 | doi = 10.1182/blood-2006-02-001594 }}
• {{cite journal | vauthors = Paradisi I, Arias S | title = IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus | journal = American Journal of Medical Genetics Part A | volume = 143 | issue = 4 | pages = 326–332 | date = Feb 2007 | pmid = 17256792 | doi = 10.1002/ajmg.a.31603 | s2cid = 22880350 }}
• {{cite journal | vauthors = Habano W, Sugai T, Jiao YF, Nakamura S | title = Novel approach for detecting global epigenetic alterations associated with tumor cell aneuploidy | journal = International Journal of Cancer | volume = 121 | issue = 7 | pages = 1487–1493 | date = Oct 2007 | pmid = 17546590 | doi = 10.1002/ijc.22847 | s2cid = 9573680 | doi-access = free }}
• {{cite journal | vauthors = Yang J, Chai L, Liu F, Fink LM, Lin P, Silberstein LE, Amin HM, Ward DC, Ma Y | title = Bmi-1 is a target gene for SALL4 in hematopoietic and leukemic cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 25 | pages = 10494–10499 | date = Jun 2007 | pmid = 17557835 | pmc = 1965541 | doi = 10.1073/pnas.0704001104 | bibcode = 2007PNAS..10410494Y | doi-access = free }}

{{refend}}

• [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=drrs GeneReviews/NCBI/NIH/UW entry on SALL4-Related Disorders]

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