Skip to main content

Advertisement

SpringerLink
Log in

Immunoexpression of SALL4 in Wilms Tumors and Developing Kidney

  • Research
  • Published:
Pathology & Oncology Research

Abstract

SALL4 is a zinc finger transcription factor that plays a role in the maintainence and pluripotency of embryonic stem cell and is important in renal development where SALL4 mutations give rise to renal malformations. Because Wilms tumor recapitulates renal embryogenesis, we hypothesized that Wilms tumor cells may also express SALL4. We performed immunohistochemistry for SALL4 on tissue microarray sections of Wilms tumors, nephrogenic rests, and fetal renal cortices. Half (26 out of 52) of the Wilms tumors showed SALL4 immunoreactivity, ranging from strong and diffuse to focal and weak. Blastemal, epithelial, and combined blastemal and epithelial patterns of immunoreactivity were identified. No cases showed stromal staining. In the fetal kidney, SALL4 expression was restricted to the blastema and primitive epithelium at 15 weeks’ gestation. SALL4 staining was not seen at later gestational ages, in non-neoplastic postnatal kidneys, or in nephrogenic rests. Our study is the first to demonstrate SALL4 immunoreactivity in Wilms tumors and in developing fetal kidney. The absence of SALL4 staining in nephrogenic rests, the presumed precursors of Wilms tumors, is intriguing and suggests that Wilms tumors have a pluripotency quality that may be lacking in nephrogenic rests.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Pode-Shakked N, Metsuyanim S, Rom-Gross E et al (2009) Developmental tumourigenesis: NCAM as a putative marker for the malignant renal stem/progenitor cell population. J Cell Mol Med 13:1792–1808

    Article  PubMed  Google Scholar 

  2. Yang J, Chai L, Fowles TC et al (2008) Genome-wide analysis reveals Sall4 to be a major regulator of pluripotency in murine-embryonic stem cells. Proc Natl Acad Sci USA 105:19756–19761

    Article  PubMed  CAS  Google Scholar 

  3. Zhang J, Tam WL, Tong GQ et al (2006) Sall4 modulates embryonic stem cell pluripotency and early embryonic development by the transcriptional regulation of Pou5f1. Nat Cell Biol 8:1114–1123

    Article  PubMed  CAS  Google Scholar 

  4. Kuhnlein RP, Frommer G, Friedrich M et al (1994) Spalt encodes an evolutionarily conserved zinc finger protein of novel structure which provides homeotic gene function in the head and tail region of the Drosophila embryo. EMBO J 13:168–179

    PubMed  CAS  Google Scholar 

  5. Kohlhase J, Taschner PE, Burfeind P et al (1999) Molecular analysis of SALL1 mutations in Townes-Brocks syndrome. Am J Hum Genet 64:435–445

    Article  PubMed  CAS  Google Scholar 

  6. Kohlhase J, Wischermann A, Reichenbach H, Froster U, Engel W (1998) Mutations in the SALL1 putative transcription factor gene cause Townes-Brocks syndrome. Nat Genet 18:81–83

    Article  PubMed  CAS  Google Scholar 

  7. Metsuyanim S, Harari-Steinberg O, Buzhor E et al (2009) Expression of stem cell markers in the human fetal kidney. PLoS ONE 4:e6709

    Article  PubMed  Google Scholar 

  8. Ma Y, Singer DB, Gozman A et al (2001) Hsal 1 is related to kidney and gonad development and is expressed in Wilms tumor. Pediatr Nephrol 16:701–709

    Article  PubMed  CAS  Google Scholar 

  9. Metsuyanim S, Pode-Shakked N, Schmidt-Ott KM et al (2008) Accumulation of malignant renal stem cells is associated with epigenetic changes in normal renal progenitor genes. Stem Cells 26:1808–1817

    Article  PubMed  CAS  Google Scholar 

  10. Chai L, Yang J, Di C et al (2006) Transcriptional activation of the SALL1 by the human SIX1 homeodomain during kidney development. J Biol Chem 281:18918–18926

    Article  PubMed  CAS  Google Scholar 

  11. Yang J, Chai L, Gao C et al (2008) SALL4 is a key regulator of survival and apoptosis in human leukemic cells. Blood 112:805–813

    Article  PubMed  CAS  Google Scholar 

  12. Al-Baradie R, Yamada K, St Hilaire C et al (2002) Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am J Hum Genet 71:1195–1199

    Article  PubMed  CAS  Google Scholar 

  13. Borozdin W, Boehm D, Leipoldt M et al (2004) SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechanism. J Med Genet 41:e113

    Article  PubMed  CAS  Google Scholar 

  14. Borozdin W, Wright MJ, Hennekam RC et al (2004) Novel mutations in the gene SALL4 provide further evidence for acro-renal-ocular and Okihiro syndromes being allelic entities, and extend the phenotypic spectrum. J Med Genet 41:e102

    Article  PubMed  CAS  Google Scholar 

  15. Kohlhase J, Chitayat D, Kotzot D et al (2005) SALL4 mutations in Okihiro syndrome (Duane-radial ray syndrome), acro-renal-ocular syndrome, and related disorders. Hum Mutat 26:176–183

    Article  PubMed  CAS  Google Scholar 

  16. Kohlhase J, Heinrich M, Schubert L et al (2002) Okihiro syndrome is caused by SALL4 mutations. Hum Mol Genet 11:2979–2987

    Article  PubMed  CAS  Google Scholar 

  17. Kohlhase J, Schubert L, Liebers M et al (2003) 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. J Med Genet 40:473–478

    Article  PubMed  CAS  Google Scholar 

  18. Miertus J, Borozdin W, Frecer V et al (2006) 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. Hum Genet 119:154–161

    Article  PubMed  CAS  Google Scholar 

  19. Terhal P, Rosler B, Kohlhase J (2006) A family with features overlapping Okihiro syndrome, hemifacial microsomia and isolated Duane anomaly caused by a novel SALL4 mutation. Am J Med Genet A 140:222–226

    PubMed  Google Scholar 

  20. Okihiro MM, Tasaki T, Nakano KK, Bennett BK (1977) Duane syndrome and congenital upper-limb anomalies. A familial occurrence. Arch Neurol 34:174–179

    PubMed  CAS  Google Scholar 

  21. Paradisi I, Arias S (2007) IVIC syndrome is caused by a c.2607delA mutation in the SALL4 locus. Am J Med Genet A 143:326–332

    PubMed  Google Scholar 

  22. Lu J, Jeong HW, Kong N et al (2009) Stem cell factor SALL4 represses the transcriptions of PTEN and SALL1 through an epigenetic repressor complex. PLoS ONE 4:e5577

    Article  PubMed  Google Scholar 

  23. Sakaki-Yumoto M, Kobayashi C, Sato A et al (2006) 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. Development 133:3005–3013

    Article  PubMed  CAS  Google Scholar 

  24. Cao D, Guo S, Allan RW, Molberg KH, Peng Y (2009) SALL4 is a novel sensitive and specific marker of ovarian primitive germ cell tumors and is particularly useful in distinguishing yolk sac tumor from clear cell carcinoma. Am J Surg Pathol 33:894–904

    Article  PubMed  Google Scholar 

  25. Cao D, Humphrey PA, Allan RW (2009) SALL4 is a novel sensitive and specific marker for metastatic germ cell tumors, with particular utility in detection of metastatic yolk sac tumors. Cancer 115:2640–2651

    Article  PubMed  CAS  Google Scholar 

  26. Cao D, Li J, Guo CC, Allan RW, Humphrey PA (2009) SALL4 is a novel diagnostic marker for testicular germ cell tumors. Am J Surg Pathol 33:1065–1077

    Article  PubMed  Google Scholar 

  27. Liu A, Cheng L, Du J et al (2010) Diagnostic utility of novel stem cell markers SALL4, OCT4, NANOG, SOX2, UTF1, and TCL1 in primary mediastinal germ cell tumors. Am J Surg Pathol 34:697–706

    PubMed  Google Scholar 

  28. Mei K, Liu A, Allan RW et al (2009) Diagnostic utility of SALL4 in primary germ cell tumors of the central nervous system: a study of 77 cases. Mod Pathol 22:1628–1636

    Article  PubMed  CAS  Google Scholar 

  29. Wang F, Liu A, Peng Y et al (2009) Diagnostic utility of SALL4 in extragonadal yolk sac tumors: an immunohistochemical study of 59 cases with comparison to placental-like alkaline phosphatase, alpha-fetoprotein, and glypican-3. Am J Surg Pathol 33:1529–1539

    Article  PubMed  Google Scholar 

  30. Ushiku T, Shinozaki A, Shibahara J et al (2010) SALL4 represents fetal gut differentiation of gastric cancer, and is diagnostically useful in distinguishing hepatoid gastric carcinoma from hepatocellular carcinoma. Am J Surg Pathol 34:533–540

    Article  PubMed  Google Scholar 

  31. Shuai X, Zhou D, Shen T et al (2009) Overexpression of the novel oncogene SALL4 and activation of the Wnt/beta-catenin pathway in myelodysplastic syndromes. Cancer Genet Cytogenet 194:119–124

    Article  PubMed  CAS  Google Scholar 

  32. Cui W, Kong NR, Ma Y, Amin HM, Lai R, Chai L (2006) Differential expression of the novel oncogene, SALL4, in lymphoma, plasma cell myeloma, and acute lymphoblastic leukemia. Mod Pathol 19:1585–1592

    Article  PubMed  CAS  Google Scholar 

  33. Ma Y, Cui W, Yang J et al (2006) SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice. Blood 108:2726–2735

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The data in this manuscript was presented at the 2010 Fall Meeting of the Society for Pediatric Pathology held in Banff, Alberta, Canada. The abstract titled “Immunohistochemical expression of SALL4 in Wilms tumors, nephrogenic rests, and fetal and postnatal renal cortices” earned Dr Jeremy Deisch the Gordon L. Vawter Award for the best presentation by a trainee.

The authors thank Ping Shang HT(ASCP)QIHC at the University of Texas Southwestern Immunohistochemistry Laboratory for the excellent immunohistochemical staining.

Author information

Authors and Affiliations

  1. Department of Pathology MC 9073, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX, 75390, USA

    Jeremy Deisch, Jack Raisanen & Dinesh Rakheja

  2. Children’s Medical Center, Dallas, TX, USA

    Dinesh Rakheja

Authors
  1. Jeremy Deisch
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jack Raisanen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dinesh Rakheja
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dinesh Rakheja.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Deisch, J., Raisanen, J. & Rakheja, D. Immunoexpression of SALL4 in Wilms Tumors and Developing Kidney. Pathol. Oncol. Res. 17, 639–644 (2011). https://doi.org/10.1007/s12253-011-9364-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12253-011-9364-0

Keywords

Search

Navigation