Overexpression of Wilms Tumor 1 Gene as a Negative Prognostic Indicator in Acute Myeloid Leukemia

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Date: Mar. 25, 2014
From: PLoS ONE(Vol. 9, Issue 3)
Publisher: Public Library of Science
Document Type: Article
Length: 6,087 words
Lexile Measure: 1530L

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Author(s): Xiaodong Lyu 1,3,*, Yaping Xin 2, Ruihua Mi 1, Jing Ding 1, Xianwei Wang 1, Jieying Hu 1, Ruihua Fan 1, Xudong Wei 1, Yongping Song 1, Richard Y. Zhao 3,*

Introduction

Acute myeloid leukemia (AML) is defined as hematopoietic stem cell malignancy characterized by clonal expansion of myeloid blasts. It is typically divided into three different risk groups, i.e , the favorable, the intermediate and the unfavorable group based on the types of chromosomal aberrations. About half (40~50%) of the AML patients have normal karyotype or normal cytogenetics that typically belong to the intermediate risk group in terms of patient's survival [1], [2]. However, inconsistencies were found among this group of patients in their responses to chemotherapy and prognosis that sometimes makes it difficult to make the right decision for therapeutic treatment and/or assessment of the possible treatment outcome of the patients.

Adding examination of molecular aberrations is thought to be helpful in addressing the differences as described above. Few molecular markers have been used to predict treatment response and prognosis in cytogenetically normal acute myeloid leukemia (CN-AML), such as the nucleoplasmin ( NPM1 ) gene and the fms-like tyrosine kinase 3 (FLT3 ) gene. A typical NPM1 gene mutation includes small insertions (4~11 bp) in the coding region of exon 12. The FLT3 gene mutations usually include a D835 point mutation in the tyrosine kinase domain (TKD) of the exon 20 or internal tandem duplications (ITD) in the exon of 14 or 15. Detection of these NPM1 and FLT3 gene mutations has been used to evaluate clinically biological behavior of leukemia cell in the CN-AML patients [2], [3].

The Wilms' tumor 1 (WT1 ) gene, which is located on the chromosome 11p13, encodes a zinc-finger transcriptional factor that has emerged as an important regulator of normal and malignant hematopoiesis. WT1 is also one of the molecules that are known to control cellular apoptosis [4]. Resistance of leukemia blasts to apoptosis may cause poor clinical outcomes. Therefore, regulation of apoptotic or anti-apoptotic pathways has high clinical relevance with regard to the remission therapy and the overall survival of the AML patients. Interestingly, high WT1 gene expression was consistently found in peripheral blood (PB) or bone marrow (BM) in the AML patients in comparison with normal controls [5]. However, the significance of WT1 overexpression in therapeutic response and prognosis are still elusive in CN-AML [6]-[8]. Goal of this study was to examine possible correlation of WT1 gene expression with therapeutic response and prognosis in the CN-AML patients. In addition, we also examined the possible interactions of WT1 gene overexpression with the NPM1 or FLT3 gene status, which are known molecular markers associated with the survival and treatment outcomes of AML patients.

Materials and Methods

Patient Population

A total of 103 CN-AML patients consisting of 58 males and 45 females with a median age of 42 years (range, 17-82 years) were recruited for the WT1 overexpression study. All patients were newly diagnosed patients with CN-AML at the Henan Cancer Hospital from the...

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Gale Document Number: GALE|A478752303