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by Jennifer Mackey. NEPHROBLASTOMA in children Discovered by Max Wilms in 1899 WT1 is a tumor suppressor 10-15% due to WT1 inactivation. Wilms’ Tumor. Kidney MRI. (Scott et al., 2001). BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!. BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!

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Wilms tumor

Wilms’ Tumor

Kidney MRI

(Scott et al., 2001)



BUT, MUTATED WT1 IS ALSO FOUND IN OTHER CANCERS!!

AND AS WE WILL SEE - IT IS NOT ALWAYS A TUMOR SUPPRESSOR!!!



Wt1 is a transcription factor
WT1 is a transcription factor

(Exon 5)

(Exon 9)

(Scholz, H. et al., 2005)



Wt1 s normal biological functions
WT1’s normal biological functions

  • Development of genitourinary system

  • Development of kidney

  • Adult kidney

  • Heart development

  • Neuron development?


WT1 KNOCKOUT MICE

  • WT1-/-

  • dies E12-birth

  • no kidneys

  • no gonads

  • severe abnormalities of retinal development

wt

KO

(Kreidberg et al., 1993)


WT1 KNOCKOUT MICE

  • WT1-/-

  • dies E12-birth

  • no kidneys

  • no gonads

  • severe abnormalities of retinal development

  • WT1+/-

  • increased mortality due to adult onset nephrotic syndrome & renal failure


WT1 is required for kidney development

(Scholz, H. et al., 2005)


ADULT KIDNEY

http://en.wikipedia.org/wiki/Image:Gray1128.png


WT1 is part of a transcriptional regulatory network

That is critical for kidney development

(Scharnhorst, V. et al., 2001)


WT1 is part of a transcriptional regulatory network

That is critical for kidney development

(Scharnhorst, V. et al., 2001)

  • WT1 TARGET GENES INVOLVED IN KIDNEY DEVELOPMENT:

  • Amphiregulin: stimulates uretic bud

  • BCL-2: encodes antiapoptotic protein

  • E-cadherin: mesenchyme condensation


WT1’s Role in Cancer

REMEMBER: WT1 = differentiation


WT1’s Role in Cancer

WT1 = PROLIFERATION!!


WT1 is a tumor suppressor

  • Wilms tumor

  • Most are sporadic and unilateral

  • 10-15% of sporadic have WT1 inactivation

  • Most others have high levels of WT1 expression

  • ~10% are bilateral and/or multifocal

http://www.sainte-justine.org/


WT1 is a tumor suppressor

  • Wilms tumor

  • Most are sporadic and unilateral

  • 10-15% of sporadic have WT1 inactivation

  • Most others have high levels of WT1 expression

  • ~10% are bilateral and/or multifocal

  • WAGR (Wilms’ tumor, Aniridia, Genitourinary abnormalities, Mental retardation)

  • Germline deletion

  • Predisposition to WT

http://en.wikipedia.org/wiki/Image:BlackEyesAniridia.jpg


WT1 is a tumor suppressor

  • Wilms tumor

  • Most are sporadic and unilateral

  • 10-15% of sporadic have WT1 inactivation

  • Most others have high levels of WT1 expression

  • ~10% are bilateral and/or multifocal

  • WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation)

  • Germline deletion

  • Predisposition to WT

  • Denys-Drash Syndrome (DDS)

  • Germline mutations (missense mutation in zinc finger domain)

  • Dominant-negative activity

  • Predisposition to WT


WT1 is a tumor suppressor

  • Wilms tumor

  • Most are sporadic and unilateral

  • 10-15% of sporadic have WT1 inactivation

  • Most others have high levels of WT1 expression

  • ~10% are bilateral and/or multifocal

  • WAGR (Wilms’ tumor, aniridia, genitourinary abnormalities, mental retardation)

  • Germline deletion

  • Predisposition to WT

  • Denys-Drash Syndrome (DDS)

  • Germline mutations (missense mutation in zinc finger domain)

  • Dominant-negative activity

  • Predisposition to WT

  • Frasier Syndrome

  • Germline point mutation in the intron 9 donor splicesite

  • Loss of KTS (-) = ratio disturbed

  • WT very rare!


…and WT1 is an Oncogene!

Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts

http://en.wikipedia.org/wiki/Image:Auer_rods.PNG


…and WT1 is an Oncogene!

Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts

Breast cancer: expression of WT1 detected in majority of BC’s evaluated

www.hopeforcancer.com/BreastCancer.html


…and WT1 is an Oncogene!

Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts

Breast cancer: expression of WT1 detected in majority of BC’s evaluated

Renal cell carcinoma: overexpression of WT1 in tubular epithelial cells in adulthood

http://en.wikipedia.org/wiki/Image:RCC.jpg


GOOD NEWS!

80% of tumors can be treated successfully!!!


References
REFERENCES

Kreidberg, Jordan A. et al. 1993. WT-1 Is Required for Early Kidney Development. Cell 74: 679-691.

Loeb, David M. and Saraswati Sukumar. 2002. The Role of WT1 in Oncogenesis: Tumor Suppressor or Oncogene? International Journal of Hematology 76: 117-126.

Scharnhorst, Volkher et al. 2001. WT1 proteins: functions in growth and differentiation. Gene 273: 141-161.

Scholz, Holger and Karin M. Kirschner. 2005. A Role for the Wilms’ Tumor Protein WT1 in Organ Development. Physiology 20: 54-59.

Scott, Carly M. et al. 2001. Wilms' Tumor: A Primary Care Case Study And Differential Diagnosis. The Internet Journal of Advanced Nursing Practice 5: Number 1.

Wagner, K-D et al. 2003. The complex life of WT1. Journal of Cell Science 116: 1653-1658.

Wagner et al. 2006. Intermediate filament protein nestin is expressed in developing kidney and heart and might be regulated by the Wilms’ tumor suppressor WT1. American Journal of Physical Regul Integr Comp Physiology 291: R779-R787.


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