Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated With Chemotherapy Resistance in Normal Karyotype Acute Myeloid Leukemia: The United Kingdom Medical Research Council Adult Leukaemia Working Party

2008 ◽  
Vol 26 (33) ◽  
pp. 5429-5435 ◽  
Author(s):  
Priya Virappane ◽  
Rosemary Gale ◽  
Robert Hills ◽  
Ioannis Kakkas ◽  
Karin Summers ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Poor Prognostic Factor ◽  
Exon 9 ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

Purpose To determine the clinical relevance of Wilms’ tumor 1 (WT1) gene mutations in acute myeloid leukemia (AML) with normal karyotype (NK). Patients and Methods Exons 7 and 9 of WT1 were screened in samples from 470 young adult NK AMLs using a combination of direct sequencing and high-resolution capillary electrophoresis. Results Overall, 51 mutations were detected in 47 cases (10%): 46 frameshift mutations with insertion/deletion of one to 28 base pairs in exon 7 (n = 45) or exon 9 (n = 1), with a median mutant level of 45% (range, 8% to 86%), and five substitutions in exon 9: D396N (n = 3), H397Y (n = 1) and H397Q (n = 1). Patients with WT1 mutations had an inferior response to induction chemotherapy compared with wild-type cases (complete remission rate, 79% v 90%, odds ratio [OR] = 3.02; 95% CI, 1.17 to 7.82; P = .02), a higher rate of resistant disease (15% v 4%; OR = 9.33; 95% CI, 2.38 to 36.6; P = .001), an increased cumulative incidence of relapse (67% v 43%, hazard ratio [HR] = 3.02; 95% CI, 1.69 to 5.38; P = .0008), with a reduction in both relapse-free survival (22% v 44%; HR = 2.16; 95% CI, 1.32 to 3.55; P = .005) and overall survival (26% v 47%; HR = 1.91; 95% CI, 1.23 to 2.95; P = .007) at 5 years. In multivariate analysis, which included FLT3 internal tandem duplication and NPM1 mutation status, the presence of a WT1 mutation remained an independent adverse prognostic factor. Conclusion WT1 mutations are a negative prognostic indicator in NK AML and may be suitable for the development of targeted therapy.

The Wilms Tumor-1 (WT1) rs2234593 variant is a prognostic factor in normal karyotype acute myeloid leukemia

2015 ◽  
Vol 95 (2) ◽  
pp. 179-190 ◽  
Author(s):  
Ahmadreza Niavarani ◽  
Stuart Horswell ◽  
Ramin Sadri ◽  
Dominique Bonnet
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Normal Karyotype ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

NPM1, IDH1/2 and DNAH11 Gene Mutations Can Improve a Prognostic Stratification of Acute Myeloid Leukemia Patients with Normal Karyotype but Not Harboring FLT3/ITD Mutation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2534-2534
Author(s):  
Yeo-Kyeoung Kim ◽  
Il-Kwon Lee ◽  
Dennis Dong Hwan Kim ◽  
Chul Won Jung ◽  
Jun-Ho Jang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Adult Patients ◽  
Npm1 Mutation ◽  
Group 3 ◽  
Group 2 ◽  
Acute Myeloid ◽  
Group 1

Abstract Abstract 2534 Background: Acute myeloid leukemia with normal karyotype (AML-NK) is known to be heterogeneous in the molecular level. Accordingly, it has become more critical to dissect this group of patients according to their prognosis using a molecular genetic technology. We attempted to analyze the incidence and prognostic implication of genetic abnormalities on survival in 426 adult patients with AML-NK. Methods: A total of 67 AML-NK patients achieved complete remission (CR), candidate mutations in 21 genes were identified by whole exome sequencing which has 41–89× coverage and by single-nucleotide polymorphism array analysis using marrow mononuclear cells at diagnosis of AML-NK. Subsequently, mutation analysis of 11 genes (i.e. FLT3/ITD, NPM1, DNMT3a, IDH1, IDH2, TET2, NRAS, WT1, DNAH11, SF3B1, and PHF6) which are known to be involved in the pathogenesis of hematologic diseases, were performed using Sanger sequencing in another subset of 359 AML-NK patients as a validation cohort. Results: Of 426 patients in total (median age: 51, ranges: 15–85), FLT3/ITD, NPM1, and DNMT3a mutations were associated with higher leukocytes counts at presentation of AML-NK. In 284 patients who received standard remission induction (RI) chemotherapy (excluding 119 patients with conservative treatment and 22 early death/1 follow-up loss after RI chemotherapy), those with FLT3/ITD mutation were significantly associated with a higher risk of relapse (p=0.02), a shorter leukemic-free survival duration (LFS)(p<0.01) or overall survival (OS) (p=0.01). Accordingly, we divided the patients into FLT3/ITD+ and FLT3/ITD− population, and analyzed their treatment outcomes according to the other mutations. In the FLT3/ITD− group (n=200), those with NPM1 mutation showed a higher CR rates after one or two cycles of RI chemotherapy (p<0.01) and a longer OS duration (p<0.01), hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.25–0.73, adjusted by other clinical variables including age, leukocyte counts at diagnosis, and transplantation (Figure 1). In the FLT3/ITD+ patients (n=84), NPM1 mutation was found to be a favorable prognostic factor showing a lower relapse rate (p=0.00), a longer LFS duration (p<0.01, HR 0.35, 95% CI 0.18–0.70), and OS duration (p=0.04, HR 0.55, 95% CI 0.31–0.98) in NPM1 mutated patients. In addition, OS was significantly different in favor of those with IDH2, especially R140Q IDH2 mutation, (p=0.04, HR 0.30, 95% CI 0.09–0.99), whereas DNAH11 mutation was associated with inferior OS (p<0.01, HR 5.78, 95% CI 1.65–20.25). Accordingly, we stratified the FLT3/ITD+ patients into three subgroups according to the NPM1, IDH1/2 and DNAH11 mutation status, Group 1: NPM1 mutation and IDH1 or 2 mutations (n=16), Group 2: isolated DNAH11 mutation (n=4) and Group 3: all mutations were negative (n=64). The group 1 showed significantly better OS than group 2 (p<0.01, HR 16.90, 95% CI 3.48–82.15) or group 3 (p<0.01, HR 3.40, 95% CI 1.20–9.55) (Figure 2). In a subgroup analysis of younger patients less than 60 years of age, similar outcomes were also observed in favor of group 1 in terms of OS (data not shown). Conclusion: Our study confirmed that NPM1 mutation is an independent prognostic factor in adult patients with AML-NK not harboring FLT3/ITD mutation. In addition, several other genetic markers were identified as prognostic including IDH1/2 or DNAH11 mutations as well as NPM1 mutation in a subgroup of AML-NK patients with FLT3/ITD mutation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CIP2A high expression is a poor prognostic factor in normal karyotype acute myeloid leukemia

Haematologica ◽  
2015 ◽  
Vol 100 (5) ◽  
pp. e183-e185 ◽  
Author(s):  
E. Barragan ◽  
M. C. Chillon ◽  
R. Castello-Cros ◽  
N. Marcotegui ◽  
M. I. Prieto ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
High Expression ◽  
Poor Prognostic Factor ◽  
Acute Myeloid

Mutation of the Wilms’ Tumor 1 Gene Is a Poor Prognostic Factor Associated with Chemoresistance in Normal Karyotype Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 361-361
Author(s):  
Priya Virappane ◽  
Rosemary E. Gale ◽  
Robert Hills ◽  
Ioannis Kakkas ◽  
Karin Summers ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Clinical Relevance ◽  
Myeloid Leukemia ◽  
Univariate Analysis ◽  
Normal Karyotype ◽  
Response To Therapy ◽  
Wild Type ◽  
Poor Prognostic Factor ◽  
Acute Myeloid

Abstract The Wilms’ tumour 1 (WT1) gene is highly expressed in various types of leukemia, suggesting a role both as a target for immunotherapy and a means for monitoring minimal residual disease. More recently WT1 has been recognised as an important mutational target in normal karyotype (NK) acute myeloid leukemia (AML), with clustering of mutations to exons 7 and 9. In this study, we set out to determine the clinical relevance of these mutations. Diagnostic DNA samples were obtained from peripheral blood or bone marrow of 470 young adult AML patients entered into the UK Medical Research Council AML 10 and 12 trials. Mutation analysis was performed using standard PCR-based direct sequencing and/or high-resolution capillary electrophoresis of exons 7 and 9. Overall, 51 mutations were observed in 47 cases (10%). Of these, 42 cases had 46 frameshift mutations arising from insertions (n=41) or deletions (n=5) of between 1 and 28 bps that would result in disruption of the C-terminal DNA binding domain of the protein. Median mutant level was 45% (range 8–86%). The remaining 5 cases were non-synonymous amino acid substitutions in exon 9, D396N (n=3) which is implicated in Denys-Drash syndrome, and 1 each of H397Y and H397Q that are of unknown functional significance. There was a borderline inverse relationship between the presence of WT1 mutations and NPM1 exon 12 mutations (p=.05), and an increased proportion of FLT3-ITDs in WT1 mutant cases (p=.08). In order to determine the clinical relevance of WT1 mutations we compared patient characteristics between WT1 mutated and WT1 wild-type cases. There was no difference between the 2 groups in age, gender, presenting WBC, or type of AML (de novo/secondary). Patients with WT1 mutations had an inferior response to therapy compared to WT1 wild-type cases (complete remission [CR] 79% Vs 90% respectively, odds ratio [OR] 3.02, 95% confidence intervals [CI] 1.17–7.82, p=.02) which was due to a higher rate of resistant disease (RD) (15% Vs 4%, OR 9.33, CI 2.38–36.6, p=.001). In univariate analysis mutated cases also had a significantly reduced disease free survival (DFS), 22% Vs 44% at 5 years (OR 2.16, CI 1.32–3.55, p=.005) and overall survival (OS), 26% Vs 47%, OR 1.91, CI 1.23–2.95, p=.007). In multivariate analysis considering age, gender, type of leukemia, WBC, FLT3-ITD and NPM1 mutant status, a WT1 mutation remained an independent adverse prognostic factor for both response to therapy (CR: OR 3.19, CI 1.25–8.13, p=.01; RD: OR 4.93, CI 1.58–15.37, p=.006) and survival (DFS: OR 1.60, CI 1.07–2.38, p=.02; OS: OR 1.52, CI 1.05–2.18, p=.03). These results indicate that WT1 mutations are an additional prognostic marker in NK AML and may be suitable for targeted therapy.

scholarly journals The Wilms Tumor-1 (WT1) rs16754 polymorphism is a prognostic factor in acute myeloid leukemia (AML): a meta-analysis

Oncotarget ◽  
2016 ◽  
Vol 7 (22) ◽  
pp. 32079-32087 ◽  
Author(s):  
Jianting Long ◽  
Shi Fang ◽  
Qiangsheng Dai ◽  
Xiaolian Liu ◽  
Wanshou Zhu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Meta Analysis ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

The Genomic Landscape of Wilms' Tumor 1 (WT1) Mutant Acute Myeloid Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 28-28
Author(s):  
Hassan Awada ◽  
Arda Durmaz ◽  
Carmelo Gurnari ◽  
Misam Zawit ◽  
Sunisa Kongkiatkamon ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Suppressor ◽  
Zinc Finger ◽  
Myeloid Leukemia ◽  
Wilms Tumor ◽  
Deletion Syndrome ◽  
Wt1 Gene ◽  
Genomic Landscape ◽  
Wilms Tumor 1 ◽  
Acute Myeloid

Mutations in tumor suppressor genes and oncogenes are both potentially therapeutically actionable in acute myeloid leukemia (AML). The Wilms' Tumor 1 (WT1) gene is located on 11p13 and encodes a zinc finger transcription factor which has been found to be overexpressed and mutated in AML. In normal development, WT1 is only expressed in a small subset of hematopoietic stem cells. While its overexpression suggests an oncogenic role, the invariable presence of mutations in the cysteine-histidine zinc finger domains indicates a tumor suppressor function, similar to that in WAGR syndrome/11p deletion syndrome in which it was first discovered. Like its unknown function in AML, the clinical significance and genetic associations of WT1 mutations have been also controversial. Although studies of WT1 mutations in AML have been conducted, the lack of solid clinical and molecular characterization of large WT1-mutant (WT1MT) AML cohort has hampered its definition. In this study, we took advantage of a compendia of genomic results from Cleveland Clinic and publicly available data of 2188 AML patients (primary (p)AML, n= 1636; secondary (s)AML, n= 433; therapy-related (t)AML, n= 119, excluding cases with acute promyelocytic leukemia, MLL-rearrangement, and core-binding factor AML). While several reports only focused on cytogenetic normal AML (CN-AML), which represented 61% of our cohort, we additionally included all other cytogenetic risk groups. In total, WT1 mutations were detected in 5% (114/2188) of patients. WT1 mutations were enriched in pAML (85%) compared to sAML (11%) and tAML (4%). Thirty-nine patients (13%) carried more than 1 WT1 mutation. WT1MT were younger [59 vs 64 years, P=0.0002] and more often females (55% vs 45%, P=0.03) as compared to WT1 wild type (WT1WT) patients. Univariate analyses of baseline parameters showed that WT1MT AML had a more proliferative phenotype with a higher WBC [15.1 vs 9.5 x109/L, P=0.03] and bone marrow blast percentages [73 vs 59%, P=0.002] and with lower platelet counts [44 vs 56 x109/L, P=0.008] compared to WT1WT cases. In the WT1MT cohort, 70% had a normal karyotype, with complex karyotype being significantly less frequent vsWT1WT patients [4 vs 16%, P=0.001]. The most common cytogenetic abnormalities in WT1MT patients included +8 (8%) followed by -9/del(9q) (3%) and -7/del(7q) (3%). Only 1 patient carried inv(3)/t(3;3) or -17/del(17p). In sum, no statistical differences in cytogenetics were found between WT1MTvsWT1WT AML patients. Next, identified mutational signatures of WT1MT patients. A panel of 44 myeloid genes and their hotspot configurations were selected according to their relevance in AML. In comparison to WT1WT AML patients, multivariate analyses showed that WT1MT patients had higher odds of biallelic CEBPA (12 vs 3%; P=0.009) and FLT3 internal tandem duplication mutations (FLT3ITD, 31 vs 16%; P=0.01) but lower odds of SRSF2 mutations (2 vs 9%, P=0.04). Since FLT3ITD has been previously described to be associated with WT1 mutations, we also focused on investigating whether mutations in the tyrosine kinase domain (TKD) were frequent in WT1MT as well. Although we found increased percentages of FLT3TKD (11%) among the WT1MT patients compared to WT1WT cohort (8%), this difference did not reach statistical significance. To uncover multifactor lesions (cytogenetic and/ or additional molecular lesions) of prognostic importance, we performed survival analyses. Although the combination of WT1 mutations and FLT3TKD shortened overall survival (OS) by 2-times in WT1MT patients vsWT1WT cases with FLT3TKD (23.7 vs 45.9 months), this result was not significant (P=0.1). In addition, the concurrent presence of other cytogenetic and molecular features didn't reveal significant impact on OS. In sum, using an adequately powered cohort, our study of the genomic landscape of WT1MT AML patients identified its genomic associations and their clinical and prognostic inferences. The application of advanced machine learning methods to large datasets of WT1MT AML patients might be crucial to capture the complex genomic interactions of WT1 gene in AML. Disclosures Carraway: BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau. Nazha:MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria.

Clinical Characteristics and Prognostic Implications of NPM1 Mutations in Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2368-2368
Author(s):  
Tatsuya Suzuki ◽  
Hitoshi Kiyoi ◽  
Kazutaka Ozeki ◽  
Akihiro Tomita ◽  
Ritsuro Suzuki ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Characteristics ◽  
Sequential Analysis ◽  
Normal Karyotype ◽  
Npm1 Mutation ◽  
Distinct Subgroup ◽  
Paired Samples ◽  
Number Of Patients ◽  
Acute Myeloid

Abstract Nucleophosmin (NPM) is a nucleolar protein with multi-functions including centromere duplication, nuclear-cytoplasmic shuttling, ribosomal biogenesis, p53 stability. NPM1 mutations were found in a large number of patients with acute myeloid leukemia (AML) especially with normal karyotype. The mutations lead to the aberrant subcellular localization of NPM protein. However, their impacts on clinical outcome remain controversial. We screened the mutations of NPM1 in 257 AML patients and analyzed the clinical significance. NPM1 mutations were found in 64 of 257 patients (24.9%). Seven types of mutations, including four novel mutations, were identified. NPM1 mutations were associated with normal karyotype, FLT3 mutations (both FLT3-ITD and D835 mutation) but not with other gene alterations such as N-RAS, p53 mutations and partial tandem duplication of the MLL gene. In 190 patients except the M3 subgroup, who were treated according to the protocol of Japan Adult Leukemia Study Group, the multivariate analysis revealed that NPM1 mutation was a favorable factor for achieving complete remission, but significantly associated with relapse. A sequential analysis, using paired samples obtained at diagnosis and relapse in 39 patients, revealed that NPM1 mutations were lost at relapse in 2 of the seventeen patients who had NPM1 mutations at diagnosis and none of the patients, who did not have NPM1 mutations at diagnosis, gained NPM1 mutations at relapse. Our results suggest that NPM-mutated AML should be a distinct subgroup with specific clinical characteristics and outcome. Loss of NPM mutations at relapse implies that NPM mutation is not necessarily a primary genetic alteration and that these leukemic clones could be sensitive to chemotherapy.

The Detection of Multilineage Dysplasia (MLD) Has No Influence on Prognosis in NPM1 Mutated Acute Myeloid Leukemia (AML) with Normal Karyotype

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2518-2518
Author(s):  
Ulrike Bacher ◽  
Susanne Schnittger ◽  
Wolfgang Kern ◽  
Tamara Weiss ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Normal Karyotype ◽  
Biological Entity ◽  
Prognostic Impact ◽  
Npm1 Mutation ◽  
Cox Regression Analysis ◽  
Multilineage Dysplasia ◽  
Acute Myeloid

Abstract Acute myeloid leukemia with mutated nucleophosmin (AML NPM1mut) represents about one-third of all adult AML and shows distinctive biological and clinical features. For this reason, AML NPM1mut is planned to be included as a separate category in the revised WHO classification. A yet controversial issue, however, is whether AML NPM1mut with or without multilineage dysplasia (MLD) may differ biologically and clinically, as the presence of MLD might confer a negative prognostic impact. A further feature that was suggested to be typical for NPM1 mutated AML is “cup-like” morphology of blasts. We here analyzed 128 pts with AML NPM1mut and normal karyotype at first manifestation (59 females, 69 males; median age 60.5 years; 23.5–79.3 y). We investigated in parallel cytomorphology from bone marrow and/or peripheral blood, chromosome banding analysis, and molecular analyses. Presence of dysplasia was defined by dysplastic features in ≥50% of cells in the respective hematopoietic lineage as defined by the WHO. A 5% cut-off was taken for the presence of “cup-like” morphology of blasts. All cases were additionally analyzed for the FLT3-ITD, and in 122 pts for the FLT3-TKD. Statistical analysis was performed for overall survival (OS), and event-free survival (EFS) according to Kaplan-Meier using the 2-sided log-rank test. Cox regression analysis related OS and EFS with the analyzed parameters. We found a predominance of the FAB M1 (21.3% of all cases), M2 (33.9%), and M4 subtypes (28.3%). Cup-like morphology in ≥5% of all blasts was observed in 39 of 127 evaluable cases (31.3%) confirming previous observations of an association of the NPM1mut and this specific blast appearance. Molecular characterization detected NPM1 mutation subtype A (n=90/122; 73.8%), B (15/122; 12.3%), and D (7/122; 5.7%), which was in accordance to previous studies. In 56 cases (43.8%) there was a coincidence with an FLT3-ITD. Dysplasia of granulopoiesis was detected in 28/126 (22.2%), of erythropoiesis in 28/104 (26.9%), and of megakaryopoiesis in 57/87 (44.5%) cases in which the respective cell lineage could be analyzed. MLD (≥2 dysplastic hematopoietic lineages) was detected in 28 of 105 evaluable cases (21.9%). Clinical follow-up was available in 104 pts. (median follow-up 12,7 months). CR rate was 83.1% in 77 evaluable pts., and median EFS was 42.1 months in 104 evaluable pts (median OS not reached). An additional FLT3-ITD had a significantly inferior OS (p=0.003) and EFS (p=0.007), confirming the present series being representative. However, the presence of MLD was not significantly related to any endpoint such as CR rate, EFS, or OS. There was no association between MLD and the NPM1-subtype. Also, there was no significant correlation of MLD and the presence of a FLT3-ITD. In conclusion, the presence of MLD in AML NPM1mut with normal karyotype had no impact on CR rate and outcome, whereas coincidence of FLT3-ITD significantly worsened prognosis. These results give further evidence that AML with NPM1mut AML is a unique biological entity with clinical course mainly influenced by FLT3-ITD coincidence. These data do not support any additional prognostic influence of MLD in this AML subtype.

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