scholarly journals Molecular study of Nucleophosmin 1(NPM1) gene in acute myeloid leukemia in Kurdish population

2021 ◽  
Vol 21 (2) ◽  
pp. 687-692
Author(s):  
Galawezh Obaid Othman ◽  
Nawsherwan Sadiq Mohammad ◽  
Chiman Hameed Saeed
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Treatment Decision ◽  
Molecular Study ◽  
Prognostic Indicators ◽  
Base Substitution ◽  
Molecular Abnormalities ◽  
Acute Myeloid

Background: In patients with Acute Myeloid Leukemia (AML) the most frequent acquired molecular abnormalities and important prognostic indicators is nucleophosmin-1 (NPM1) mutations. Our study aims was molecular study of Nucleop- hosmin -1 gene in Acute Myeloid Leukemia in Kurdish population. Patients &Methods: A total of 50 patients with AML, (36) of them attended Nanakaly Hospital and (14) attended Hiwa Hospital and 30 healthy subjects as control were selected randomly, all were matched of age and gender. Polymerase chain reaction (PCR) was used for detection of NPM1 gene mutation. Three samples of PCR product for NPM1 gene mutations were sequenced, and mutations were determined by comparison with the normal NPM1 sequence NCBI (GenBank acces- sion number NM_002520). Results: Out of 50 patients with AML, 5 (10%) of them were NPM1 gene mutation positive, and 45 (90%) were negative. The mutation were a base substitution (C to A), (G to C), (G to T), transversion mutation in addition of frame shift mutation and all mutated cases were heterozygous and retained a wild type allele. Conclusion: Identification of NPM1 mutations in AML are important for prognostication, treatment decision and optimi- zation of patient care. Keywords: Acute myeloid leukemia; Nucleophosmin-1 (NPM-1) gene mutation; PCR.

The Impact of Novel Molecular Markers on Risk Stratification in Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-33-SCI-33 ◽  
Author(s):  
Bob Löwenberg ◽  
Peter Valk ◽  
Ivo P. Touw ◽  
Ruud Delwel
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Risk ◽  
Gene Mutations ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Molecular Abnormalities ◽  
Genome Wide ◽  
The Impact ◽  
Acute Myeloid

Abstract Abstract SCI-33 The treatment of acute myeloid leukemia (AML) remains associated with considerable failure rates. From a therapy viewpoint AML presents as a kaleidoscope of highly diverse diseases for which the (epi)genetic heterogeneity of the disease is the overriding determinant of treatment failure. Diverse coemerging molecular abnormalities (gene mutations, expression abnormalities) related, for instance, to the genes CEBPA, nucleophosmin-1, FLT-3, RUNX1, ASXL1, P53, G-CSF-R, IDH1/IDH2, DNMT3A, and EVI-1 in variable composite configurations, determine the considerable “interindividual” and “intraindividual” variations of AML. As these somatic genetic abnormalities in transformed hematopoietic progenitor cells perturb critical cellular pathways and functions, they confer a profound impact upon the clinical phenotype of the disease—and also may define unique diagnostic subtypes (diagnosis) and therapeutic resistance (treatment response). Using genome-wide approaches and well-defined cohorts, the identified molecular biomarkers provide insights into the variability of treatment outcome, and furnish an informative framework for risk-adapted treatment decisions according to disease risk and therapeutic responsiveness (prognosis and treatment choice). In this presentation, examples of strategies to assess the prognostic impact of genomic abnormalities will be discussed, as well as the challenge to integrate the numerous markers into meaningful decision algorithms that can be used for more individualized therapy choices, for example, regarding the use of particular therapeutic agents and the utility (risk-benefit) of allogeneic stem cell transplantation. Disclosures: Löwenberg: Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Cutting Edge Molecular Therapy for Acute Myeloid Leukemia

2020 ◽  
Vol 21 (14) ◽  
pp. 5114
Author(s):  
Kenichi Miyamoto ◽  
Yosuke Minami
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Treatment Decision ◽  
Molecular Therapy ◽  
Treatment Decision Making ◽  
Whole Exome ◽  
Therapeutic Development ◽  
Approved Drugs ◽  
Acute Myeloid

Recently, whole exome sequencing for acute myeloid leukemia (AML) has been performed by a next-generation sequencer in several studies. It has been revealed that a few gene mutations are identified per AML patient. Some of these mutations are actionable mutations that affect the response to an approved targeted treatment that is available for off-label treatment or that is available in clinical trials. The era of precision medicine for AML has arrived, and it is extremely important to detect actionable mutations relevant to treatment decision-making. However, the percentage of actionable mutations found in AML is about 50% at present, and therapeutic development is also needed for AML patients without actionable mutations. In contrast, the newly approved drugs are less toxic than conventional intensive chemotherapy and can be combined with low-intensity treatments. These combination therapies can contribute to the improvement of prognosis, especially in elderly AML patients who account for more than half of all AML patients. Thus, the treatment strategy for leukemia is changing drastically and showing rapid progress. In this review, we present the latest information regarding the recent development of treatment for AML.

scholarly journals Gene Mutation Profile and Risk Stratification in AML1-ETO-Positive Acute Myeloid Leukemia Based on Next-Generation Sequencing

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5249-5249
Author(s):  
Guopan Yu ◽  
Changxin Yin ◽  
Fuqun Wu ◽  
Ling Jiang ◽  
Zhongxin Zheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Gene Mutations ◽  
Kit Mutation ◽  
Mutation Profile ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Gene mutations play a critical role in leukemogenesis of AML1-ETO-positive acute myeloid leukemia (AE-AML). Nevertheless, gene mutation profile in this subtype leukemia remains unclear, and their clinical effect might be underestimated. In this study, we detested gene mutations at diagnosis and relapse with next-generation sequencing in 64 newly diagnosed AE-AML patients, and verified the results with Sanger sequencing at the same time. Our results showed that 68.8% patients presented recurrent mutations at diagnosis and 6/11 cases underwent genetic alterations at relapse. C-KIT mutation was the most common event at diagnosis, with an incidence of 42.2%, followed by ASXL1 (15.6%), MET (12.5%), MLH1 (9.4%) , TET2 (7.8%), and FBXW7, TP53 and DNMT3A (7.8%), etc. Also, C-KIT mutation was the most common molecular event associated with relapse (7/11, 63.6%). No significant difference in the clinical characteristic between the gene mutation and wild type (WT) groups was observed, except of higher incidence of additional cytogenetic abnormalities (ACAs) (P=0.025) in TP53 mutation patients. C-KIT (exon 8, 17) mutation but not exon 10 adversely affected on survival. Also ASXL1 and TP53 mutation were poor for the RFS (P<0.05), and ASXL1, MET, FBXW7 and TP53 mutation negatively impacted on the OS (P<0.05). Multivariate analysis showed C-KIT (exon 8, 17) and ASXL1 mutations were the independent adverse factors for survival. Further, co-mutation of these two genes showed even worse effect on survival. Taking together, additional gene mutations are critical in the development and progression of AE-AML. C-KIT and ASXL1 mutations are the two most common molecular events in this subtype leukemia. Single mutation of C-KIT (exon 8, 17) or ASXL1 poorly affects on survival, even worse in the co-mutation. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular Study of FLT3 gene mutations in Acute Myeloid Leukemia from Pakistan : Correlation with clinicopathological parameters.

2019 ◽  
Vol 4 (4) ◽  
pp. 81-84
Author(s):  
Mariam Faiz ◽  
Farzana Rashid
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
Gene Mutations ◽  
Molecular Study ◽  
Kinase Domain ◽  
Clinicopathological Parameters ◽  
Tyrosine Kinase Domain ◽  
Female Ratio ◽  
Acute Myeloid

Introduction: FLT3 mutations are common genetic changes reported to have prognostic significance in acute myeloid leukemia (AML). Bone marrow/peripheral blood samples of 63 AML Pakistani patients were collected and DNA was isolated.Materials and Methods: The FLT3 internal tandem duplication (ITD) and the D835 activating mutation in the tyrosine kinase domain (TKD) were analyzed by polymerase chain reaction (PCR).Results: Among 63 AML patients, 42 were males and 21 were females with male to female ratio 2.1:1. The age ranged between 15 to 75 years with a median age of 32 years. AML-M2 was the predominant French-American-British (FAB) subtype (32%) followed by M3 (27%), M4 (19%), M5 (6.3%) and M1 (6.3%). The incidence of FLT3/ITD and TKD was 22% and 6.3% respectively. Majority of the FLT3/ITD mutation were detected in AML-M4 (38%) patients while D835 mutation was common in both FAB M1, M2. Presence of mutation was significantly associated with age but significance was not achieved for hyperleukocytosis.Conclusion: This study constitutes the first report from Pakistan reporting significant presence of FLT3/ITD mutations in our adult AML patients with different FAB subtypes Molecular mutation analysis in different cytogenetic groups with follow-up is required to understand the pathogenesis of leukemias and their role as a valuable prognostic marker in our patients.

Nucleophosmin Gene Mutations Identify a Favorable Risk Group in Childhood Acute Myeloid Leukemia with a Normal Karyotype.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 366-366
Author(s):  
Iris H. Hollink ◽  
Christian M. Zwaan ◽  
Marry M. van den Heuvel-Eibrink ◽  
Martin Zimmerman ◽  
Susan Arentsen-Peters ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Normal Karyotype ◽  
Type A ◽  
Prognostic Impact ◽  
Wild Type ◽  
Molecular Abnormalities ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Exon 12 gene mutations in nucleophosmin (NPM1) were recently discovered in approximately 30% of adult acute myeloid leukemia (AML) samples, and cluster in the normal karyotype subgroup (NK-AML). NPM1-mutated adult NK-AML has a favorable outcome (pOS in the 40-50% range), but in case a FLT3 internal tandem duplication (FLT3/ITD) is also present outcome is worse with 25–30% pOS. In pediatric AML, NPM1 mutations are less frequent (6–8%; Cazzaniga, Blood 2005 & Brown, Blood 2007). No studies have specifically addressed pediatric NK-AML, a subgroup lacking favorable prognostic cytogenetic aberrations and therefore mostly stratified in the intermediate risk arm of pediatric AML treatment protocols. We screened 292 newly diagnosed AML samples, and detected NPM1 mutations in 25 cases (8.6%). We also screened 46 initial diagnosis-relapse pairs, and no clonal instability was observed, which suggests that NPM1 mutations may be used for minimal residual disease detection. In contrast to adults, where type A mutations (TCTG-insertion) are most frequent (80%), in our cohort type B (CATG-insertion) mutations were found in 39% and type A in 23%. In the NK-AML cohort (n=98), 20% was NPM1-mutated, which was age dependent: &lt;3 years, 0%; 3–10 years, 19%; &gt;10 years, 29% (p=0.04). None of the 10 FAB M5 cases was NPM1 mutated (p=0.09). NPM1 mutations had an independent favorable prognostic impact on outcome in patients with NK-AML (5-year pEFS 77% vs. 41% for wild type patients; p=0.003), irrespective of FLT3 mutational status. In fact, NPM1-mutated patients with a FLT3/ITD did better than patients without an ITD, although this was not statistically significant (5-year pEFS 90% vs. 63%, respectively; p=0.48). In NK-AML without NPM1 mutations, patients with FLT3/ITD positive AML did significantly worse than wild type FLT3 AML patients (5-year pEFS 18% vs. 52%, p=0.002). The differential prognostic impact of FLT3/ITD between the NPM1-mutated vs. the wild type patients was not caused by differences in the FLT3/ITD allelic ratio or ITD length, nor was there a relationship with the type of NPM1 mutations. Multivariate analysis, including age, white blood cell count, NPM1 and FLT3 status and stem cell transplantation as time-dependent co-variable, showed that only NPM1 mutations had independent prognostic significance for pEFS (RR 0.34, p=0.02). We conclude that the incidence of NPM1 mutations increases with age, and that NPM1 mutations define a subgroup with favorable prognosis in pediatric NK-AML. Our data suggest that these molecular abnormalities allow stratification of children with NK-AML. However, different from adult NK-AML, we observed that all children with NPM1 mutations did well, irrespective of FLT3 status. Therefore, treatment in the ‘good risk’ arm should be considered for children with NPM1-mutated NK-AML.

Nucleophosmin Gene Mutations in Acute Myeloid Leukemia

2006 ◽  
Vol 130 (11) ◽  
pp. 1687-1692
Author(s):  
Weina Chen ◽  
Georgios Z. Rassidakis ◽  
L. Jeffrey Medeiros
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Nuclear Export ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Chemotherapeutic Agents ◽  
Detection Methods ◽  
Heterozygous Mutation ◽  
Age Difference ◽  
Acute Myeloid

Abstract Context.—Heterozygous mutation of the nucleophosmin gene (NPM1) has recently been described as one of the most frequent genetic lesions in acute myeloid leukemia (AML). Objective.—(1) To discuss the clinical, morphologic, immunophenotypic, and genetic features of AML with NPM1 gene mutations, along with various detection methods, (2) To explore the mechanisms by which NPM1 gene mutations contribute to leukemogenesis. Data sources/extraction.—Data were analyzed from 7 recently published papers. Results.—NPM1 gene mutations tend to occur more frequently in women, and also tend to be associated with a higher white blood cell count. There is no significant age difference. NPM1-mutated AML is preferentially associated with AML with monocytic differentiation (in particular FAB M5b), lack of CD34, normal cytogenetics, FLT3 gene mutations, and a trend toward favorable clinical outcome, especially in patients without FLT3 gene mutation. NPM1 gene mutations cause a frame shift in the C-terminus of exon 12, disrupting the NPM nucleolar-localization signal or generating a leucine-rich nuclear export motif, resulting in abnormal cytoplasmic accumulation of NPM. Several methods are suitable for detecting NPM1 gene mutation, including molecular and immunohistochemical studies. These mutations may contribute to leukemogenesis, at least in part, through disruption of the p14ARF (alternative reading frame) MDM2-p53 pathway and centrosomal duplication. Conclusions.—Detection of NPM1 gene mutations may allow dissection of the heterogeneous group of AML with normal karyotype into prognostically different subgroups. Exploring the mechanisms may lead to a better understanding of how mutant NPM protein becomes leukemogenic, thereby providing insights for the development of new chemotherapeutic agents.

C/Ebpa Gene Mutation and C/Ebpa Promoter Hypermethylation in Acute Myeloid Leukemia with Normal Cytogenetics.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1570-1570
Author(s):  
Ying Lu ◽  
Wengang Chen ◽  
Wei Chen ◽  
Anthony Stein ◽  
Lawrence M. Weiss ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Promoter Hypermethylation ◽  
Granulocytic Differentiation ◽  
Npm1 Mutation ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Abstract 1570 Poster Board I-594 Acute myeloid leukemia with normal cytogenetics (CN-AML) represents approximately 40-50% of de novo AML cases and constitutes the single largest cytogenetic group of AML. CN-AML is composed of a heterogeneous group of AML considered to be more or less in the intermediate prognostic category. Stratified prognostic determinants are required to predict which patients in this heterogeneous category have an increased risk of relapse, resistance to therapy or long term disease outcomes. The CCAAT enhancer binding protein alpha (C/EBPA) is a key transcription factor involved in regulation of granulocytic differentiation and myelopoiesis. In the past few years, various studies have suggested that C/EBPA is negatively regulated in certain AML patients. Impairments in C/EBPA signaling such as gene mutation, transcriptional dysregulation, as well as epigenetic modification via promoter hypermethylation have been identified in CN-AML and these alterations may play an important role in pathogenesis and may predict prognosis in these patients. In the current study, we investigated C/EBPA gene mutations and promoter hypermethylation in a series of 53 patients with CN-AML. In addition, we also analyzed two other frequent mutations (FLT3/ITD and NPM1) in these patients and correlated them with C/EBPA gene alterations. Genomic DNA was isolated from diagnostic bone marrow and peripheral blood samples. The C/EBPA gene mutations were detected by PCR amplification followed by direct DNA sequencing while the promoter hypermethylation was characterized by methylation-specific PCR analysis. The FLT3/ITD mutation and NPM1 mutation were detected by using multiplex PCR followed by capillary electrophoresis. The study included 28 female patients and 25 male patients, all adults, with a median age of 49 years. 13/53 (24.5%) patients were FLT3/ITD+/NPM1-, 11/53 (20.8%) patients were FLT3/ITD+/NPM1+, 9/53 (17.0%) patients were FLT3/ITD-/NPM1+, and 20/53 (37.7%) patients were FLT3/ITD-/NPM1-. Four out of the 53 cases (7.5%) displayed C/EBPA mutations, whereas 49 (92.5%) cases had only C/EBPA wild-type alleles. Of the 4 positive cases, three patients had N-terminal mutations only, while one patient had mutations in both the N- and C-terminal region. Two of the 4 positive cases also harbored both FLT3/ITD and NPM1 mutation simultaneously, while the other two patients had neither FLT3/ITD nor NPM1 mutations. In addition, 7 (13.2%) of the 53 cases displayed C/EBPA promoter hypermethylation. Interestingly they were all in CN-AML cases without FLT3/ITD or NPM1 mutations. None of the 7 patients with C/EBPA promoter hypermethylation showed C/EBPA mutation. In conclusion, C/EBPA mutation and promoter hypermethylation can be detected at a relatively low frequency in de novo CN-AML patients, suggesting they may contribute to leukemogenesis. C/EBPA mutation appears to be frequently seen “high-risk” AML (FLT3/ITD+/NPM1+; FLT3/ITD+/NPM1- or FLT3/ITD-/NPM1-), while C/EBPA hypermethylation appears to be more common in AML with FLT3/ITD- /NPM1- and is not associated with C/EBPA mutation. The clear prognostic relationship of C/EBPA alteration and FLT3/ITD, NPM1 mutation needs to be further validated. Disclosures No relevant conflicts of interest to declare.

The Prognostic Impact Of Complex Gene Mutation In The Intermediate Risk Karyotype Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1418-1418
Author(s):  
Satoshi Wakita ◽  
Hiroki Yamaguchi ◽  
Takeshi Ryotokuji ◽  
Tuneaki Hirakawa ◽  
Ikuko Omori ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Nippon Medical School ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Background Many gene mutations were detected and overlapped in de novo acute myeloid leukemia (AML), but the prognosis of complex gene mutation remains to be unclear. In this study, we analyzed the prognostic impact of complex gene mutation in de novo AML patients with the intermediate risk karyotype. Methods We analyzed 143 samples from de novo AML patients with the intermediate risk karyotype diagnosed at Nippon Medical School Hospital from 2000 to 2012. Bone marrow or peripheral blood samples containing 20% or more blast cells were used for analyses. Mutation analyses were performed using PCR method for FLT3-ITD, FLT3-TKD and MLL-PTD, and direct sequence for NPM1, C/EBPα, DNMT3a, IDH1/2, TET2 and N/K-RAS. Results The NPM1 (39.9%), DNMT3a (26.6%), FLT3-ITD (24.5%), IDH1/2 (18.9%), TET2 (17.5%), C/EBPα (14.7%), N/K-RAS (14.0%) and MLL-PTD (6.3%) mutations were detected in our cohort, respectively. When we performed prognostic analyses for mutations of these genes, DNMT3 mutation and FLT3-ITD were isolated as a poor prognostic factor in overall survival (OS) , respectively (DNMT3a mutation positive: n=39, 3yOS 17.9%. negative: n=104, 3yOS 33.2%. p=.0056) (FLT3-ITD positive: n=35, 3yOS 12.2%. negative: n=108, 3yOS 35.0%. p=.0077). Moreover, in the FLT3-ITD positive cases, OS of patients with DNMT3a R882 mutation was significantly shorter than those without R882 mutation (R882 positive: n=20, 3yOS: 0%. negative: n=15, 3yOS 25.0%. p<.0256). Interestingly, High rate of patients with FLT3-ITD (91.4%), NPM1 (89.5%), DNMT3a (92.1%), TET2 (84.0%), and IDH1/2 (88.9%) mutations were detected other overlapped mutations, respectively. The frequency of the overlapped mutations in patients with DNMT3a mutation, especially with mutations on R882, was significantly higher than those in patients without them (DNMT3a: p=.0001, R882: p<.0001). For total cohort, the rates of and OS and relapse free survival (RFS) in patients with three or more overlapping mutations (complex gene mutation: CGM) were significantly lower than those in patients without them (CGM+: n=36, 3yOS 5.6%. CGM-: n=107, 3yOS 37.7%. p<.0001) (CGM+: n=12, 3yRFS: 8.3%. CGM-: n=57, 3yRFS: 36.0%. p=.0013). Moreover, among the patients without FLT3-ITD, the rates of RFS and OS at 3 years in patients with complex gene mutation were significantly lower than those in patients without them (CGM+: n=11, 3yOS 5.6%. CGM-: n=96, 3yOS 37.7%. p<.0408) (CGM+: n=4, 3yRFS: 8.3%. CGM-: n=51, 3yRFS: 36.0%. p=.0179). Conclusions Our study revealed that the gene mutations appeared to be overlapped, and the complex gene mutation significantly affected the prognosis of de novo AML with the intermediate risk karyotype. Intriguingly the DNMT3a mutation may contribute to an occurrence of complex gene mutation by giving genetic instability to AML cells. Disclosures: No relevant conflicts of interest to declare.

Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
A.M. Radzhabova ◽  
S.V. Voloshin ◽  
I.S. Martynkevich ◽  
A.A. Kuzyaeva ◽  
V.A. Shuvaev ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Course Of Disease ◽  
Acute Myeloid
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