Simultaneous detection of MDR1 and WT1 gene expression to predict the prognosis of adult acute lymphoblastic leukemia

Xu, Bing; Song, Xingguo; Yip, Nga Chi; Xiao, Pengnan; Zhang, Yanyan; Wang, Weiguang; Zhou, S. Kevin

doi:10.1179/102453310x12583347009937

Cited by 13 publications

(9 citation statements)

References 28 publications

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“…To our knowledge, this is the first such report for the Ph-like ALL subset. Likewise, we found amplified WT1 expression in primary leukemia cells from 123 pediatric BCR-ABL/Ph + patients thereby confirming and extending an earlier report of high WT1 expression in adult BCR-ABL/Ph + ALL [12] . Finally, our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primarily leukemia cells from newly diagnosed B-lineage ALL patients (P = 0.001).…”

Section: Discussionsupporting

confidence: 91%

“…The protein product of the WT1 gene is a zinc-finger transcription factor and a tumorassociated antigen. WT1 protein is abundantly expressed in numerous hematological malignancies, including acute myeloid leukemia (AML) [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18] . While WT1 is an intracellular protein, WT1-derived peptides are expressed on the surface of cancer cells in the context of human leukocyte antigen (HLA) Class I antigens.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast to AML, there is a paucity of knowledge regarding the expression of WT1 antigen in acute lymphoblastic leukemia (ALL). Only a few studies with relatively small patient numbers have evaluated WT1 expression in ALL [8][9][10]12] and there is no active interventional clinical trial evaluating the clinical potential of a WT1-targeting therapeutic platform in ALL patients. The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric ALL.…”

Section: Introductionmentioning

confidence: 99%

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Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Uçkun¹

2018

CDR

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Aim: The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia (ALL). Methods: We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells vs. primary leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL cases. We also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159, GSE13351, and GSE13159. Results: Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements (MLL-R) express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ALL. Notably, MLL-R + patients exhibited > 6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined (P < 0.0001). Our findings in 97 MLL-R + infant B-lineage ALL cases uniquely demonstrated that WT1 is expressed at 1.5-4.2-fold higher levels in MLL-R + infant leukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow cells. Furthermore, our study demonstrates for the first time that the WT1-regulated EWSR1 , TP53 , U2AF2 , and WTAP genes (i.e., WT1 interactome) were differentially upregulated in MLL-R + leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R + pediatric B-lineage ALL. These novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R + pediatric B-lineage ALL, including MLL-R + infant ALL. Furthermore, our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had significantly higher WT1 expression when compared to normal hematopoietic cells. Finally, our findings demonstrate for the first time that chemotherapy-resistant primarily leukemic cells from relapsed B-lineage ALL patients exhibit higher expression levels of WT1 than primary leukemia cells from newly diagnosed B-lineage ALL patients (P = 0.001). Conclusion: Our findings indicate that the WT1 gene product may serve as a target for immunotherapy in high risk/poor prognosis subsets of newly diagnosed as well as relapsed pediatric B-lineage ALL. Our findings also significantly expand the current knowledge of WT1 expression in T-lineage ALL and provide new evidence that WT1 gene and its interactome are expressed in T-lineage ALL cells at significantly higher levels than in normal hematopoietic cells. This previously unknown differential expression profile uniquely indicates that the protein product of WT1 would be an attractive molecular target for treatment of T-lineage ALL as well.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Uçkun¹

2018

CDR

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“…Among the genes in the subnetworks, some are known to be associated with T-ALL from previous studies: ABL1 [1, 56, 57], CCL5 [58], CD99 [59], TP53 [60], and WT1 [61, 62]. Table 3 exhibits these T-ALL related genes and their behavior.…”

Section: Resultsmentioning

confidence: 99%

Identification of Interconnected Markers for T-Cell Acute Lymphoblastic Leukemia

Guven-Maiorov

Keskin

et al. 2013

BioMed Research International

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T-cell acute lymphoblastic leukemia (T-ALL) is a complex disease, resulting from proliferation of differentially arrested immature T cells. The molecular mechanisms and the genes involved in the generation of T-ALL remain largely undefined. In this study, we propose a set of genes to differentiate individuals with T-ALL from the nonleukemia/healthy ones and genes that are not differential themselves but interconnected with highly differentially expressed ones. We provide new suggestions for pathways involved in the cause of T-ALL and show that network-based classification techniques produce fewer genes with more meaningful and successful results than expression-based approaches. We have identified 19 significant subnetworks, containing 102 genes. The classification/prediction accuracies of subnetworks are considerably high, as high as 98%. Subnetworks contain 6 nondifferentially expressed genes, which could potentially participate in pathogenesis of T-ALL. Although these genes are not differential, they may serve as biomarkers if their loss/gain of function contributes to generation of T-ALL via SNPs. We conclude that transcription factors, zinc-ion-binding proteins, and tyrosine kinases are the important protein families to trigger T-ALL. These potential disease-causing genes in our subnetworks may serve as biomarkers, alternative to the traditional ones used for the diagnosis of T-ALL, and help understand the pathogenesis of the disease.

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“…Patients with high expressions of WT1 mRNA exhibited shorter overall survival and disease-free survival periods, and the increase in the WT1 mRNA level in the BM related to the significantly increased risk of relapse. Therefore, WT1 mRNA has been reported to be a useful indicator in predicting prognosis [23][24][25].…”

Section: Introductionmentioning

confidence: 99%

Clinical Significance of Wt1 mRNA Levels in Japanese Acute Lymphoblastic Leukemia Patients

Hashii¹,

Kosaka²,

Watanabe³

et al. 2017

J Leuk

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Simultaneous detection of MDR1 and WT1 gene expression to predict the prognosis of adult acute lymphoblastic leukemia

Cited by 13 publications

References 28 publications

Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Wilms’ tumor gene (WT1) is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

Identification of Interconnected Markers for T-Cell Acute Lymphoblastic Leukemia

Clinical Significance of Wt1 mRNA Levels in Japanese Acute Lymphoblastic Leukemia Patients

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