WT1: Wilms’ Tumor gene by Jennifer Mackey

Wilms’ Tumor o NEPHROBLASTOMA in children o Discovered by Max Wilms in 1899 o WT1 is a tumor suppressor o 10-15% due to WT1 inactivation 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 alternatively spliced to make many protein isoforms (Wagner, K.D. et al., 2003)

WT1 is a transcription factor (Scholz, H. et al., 2005) (Exon 9)(Exon 5)

WT1 is a transcription factor

WT1’s normal biological functions o Development of genitourinary system o Development of kidney o Adult kidney o Heart development o Neuron development?

WT1 -/- dies E12-birth no kidneys no gonads severe abnormalities of retinal development wtKO (Kreidberg et al., 1993)

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

(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 is part of a transcriptional regulatory network That is critical for kidney development WT1 TARGET GENES INVOLVED IN KIDNEY DEVELOPMENT: Amphiregulin: stimulates uretic bud BCL-2: encodes antiapoptotic protein E-cadherin: mesenchyme condensation

REMEMBER: WT1 = differentiation

WT1 = PROLIFERATION!!

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

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

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

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 splice site Loss of KTS (-) = ratio disturbed WT very rare!

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

Acute myeloid leukemia(AML): WT1 overexpressed in leukemic blasts Breast cancer: expression of WT1 detected in majority of BC’s evaluated

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

80% of tumors can be treated successfully!!!

REFERENCES Kreidberg, Jordan A. et al WT-1 Is Required for Early Kidney Development. Cell 74: Loeb, David M. and Saraswati Sukumar The Role of WT1 in Oncogenesis: Tumor Suppressor or Oncogene? International Journal of Hematology 76: Scharnhorst, Volkher et al WT1 proteins: functions in growth and differentiation. Gene 273: Scholz, Holger and Karin M. Kirschner A Role for the Wilms’ Tumor Protein WT1 in Organ Development. Physiology 20: Scott, Carly M. et al 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 The complex life of WT1. Journal of Cell Science 116: Wagner et al 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.