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WT1
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Interpretation 44
Tier 2
WT1
Variants
WT1 any mutation
Primary Sites
Blood
Bone Marrow
Tumor Types
Acute Myeloid Leukemia
Acute Leukemia of Unspecified Cell Type
Anemia, Unspecified
Atypical Chronic Myeloid Leukemia
B Lymphoblastic Leukemia/Lymphoma
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Chronic Neutrophilic Leukemia
Cytopenia
Eosinophilia
Essential Thrombocythemia
Histiocytic and Dendritic Cell Neoplasms
Langerhans Cell Histiocytosis
Leukocytosis
Leukopenia
Mast Cell Neoplasm
MDS with Ring Sideroblasts
Monocytosis
Myelodysplastic Syndrome
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Myeloid Neoplasm
Other Acute Leukemia
Polycythemia Vera
Polycythemia
Primary Myelofibrosis
T Lymphoblastic Leukemia/Lymphoma
Thrombocytopenia, Unspecified
Thrombocytosis
Interpretation

WT1 encodes for a transcription factor containing an N-terminal transactivation domain and a C-terminal zinc-finger domain necessary for the development of the urogenital system. The precise roles of WT1 in normal and malignant hematopoiesis remain uncertain. New emerging supports a novel role of WT1 in the regulation of epigenetic programs through its interaction with TET proteins in the 5=hydroxymethylation of cytosines. WT1 mutations are found in 6% of acute myeloid leukemia overall, and about 8-13% in cytogenetically normal AML. Higher frequencies are present in biallelic CEBPA mutated acute myeloid leukemia (14%), followed by t(15;17)/PML-RARA (11.0%), and FLT3-ITD (8.5%,). WT1 mutations are associated with younger age in AML. WT1 mutations are typically putative loss of function mutations and most frequently occur in exon 7 or exon 9. About 75% of these mutations are frameshift, and the remaining are missense, nonsense, splice site or inframe indel mutations. In some cases two or more mutations in WT1 may occur. In addition, WT1 mutations may coexist with mutations in NPM1, FLT3, among others. WT1 is overexpressed in the majority of AML, giving rise to the concept that it may act as both a tumor suppressor and oncogene, depending on the context. Several studies showed that WT1 mutations are associated with a worse prognosis in cytogenetically normal acute myeloid leukemia, although one study including patients from three German-Austrian AML study protocols demonstrated no association with overall survival or relapse-free survival. Given its over-expression in AML, clinical trials employing peptide vaccination strategy against WT1 has been ongoing in AML patients.

Citations
  1. Paschka P, et al. Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 2008;26(28):4595-602
  2. Hou HA, et al. Integration of cytogenetic and molecular alterations in risk stratification of 318 patients with de novo non-M3 acute myeloid leukemia. Leukemia 2014;28(1):50-8
  3. Gaidzik VI, et al. Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 2009;113(19):4505-11
  4. Marlton P The many facets of WT1 in acute myeloid leukemia: clarity remains elusive. Leuk Lymphoma 2014;55(2):235-7
  5. Krauth MT, et al. WT1 mutations are secondary events in AML, show varying frequencies and impact on prognosis between genetic subgroups. Leukemia 2015;29(3):660-7
  6. Rampal R, et al. Wilms tumor 1 mutations in the pathogenesis of acute myeloid leukemia. Haematologica 2016;101(6):672-9
  7. Hou HA, et al. WT1 mutation in 470 adult patients with acute myeloid leukemia: stability during disease evolution and implication of its incorporation into a survival scoring system. Blood 2010;115(25):5222-31
Last updated: 2019-08-28 14:54:01 UTC
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When using PMKB, please cite: Huang et al., JAMIA 2017


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