scholarly journals In Silico Genetics Revealing Novel Mutations inCEBPAGene Associated with Acute Myeloid Leukemia

2019 ◽  
Author(s):  
Mujahed I. Mustafa ◽  
Zainab O. Mohammed ◽  
Naseem S. Murshed ◽  
Nafisa M. Elfadol ◽  
Abdelrahman H. Abdelmoneim ◽  
...  

AbstractBackgroundMyelodysplastic syndrome/Acute myeloid leukemia (MDS/AML) is a highly heterogeneous malignant disease; affects children and adults of all ages. AML is one of the main causes of death in children with cancer. However, It is the most common acute leukemia in adults, with a frequency of over 20 000 cases per year in the United States of America alone.MethodsThe SNPs were retrieved from the dbSNP database. this SNPs were submitted into various functional analysis tools that done by SIFT, PolyPhen-2, PROVEAN, SNAP2, SNPs&GO, PhD-SNP and PANTHER, while structural analysis were done by I-mutant3 and MUPro. The most damaging SNPs were selected for further analysis by Mutation3D, Project hope, ConSurf and BioEdit softwares.ResultsA total of five novel nsSNPs out of 248 missense mutations were predicted to be responsible for the structural and functional variations of CEBPA protein.ConclusionIn this study the impact of functional SNPs in the CEBPA gene was investigated through different computational methods, which determined that (R339W, R288P, N292S N292T and D63N) are novel SNPs have a potential functional effect and can thus be used as diagnostic markers and may facilitate in genetic studies with a special consideration of the large heterogeneity of AML among the different populations.

2019 ◽  
Vol 18 ◽  
pp. 117693511987081
Author(s):  
Mujahed I Mustafa ◽  
Zainab O Mohammed ◽  
Naseem S Murshed ◽  
Nafisa M Elfadol ◽  
Abdelrahman H Abdelmoneim ◽  
...  

Background: Acute myeloid leukemia (AML) is an extremely heterogeneous malignant disorder; AML has been reported as one of the main causes of death in children. The objective of this work was to classify the most deleterious mutation in CCAAT/enhancer-binding protein-alpha ( CEBPA) and to predict their influence on the functional, structural, and expression levels by various Bioinformatics analysis tools. Methods: The single nucleotide polymorphisms (SNPs) were claimed from the National Center for Biotechnology Information (NCBI) database and then submitted into various functional analysis tools, which were done to predict the influence of each SNP, followed by structural analysis of modeled protein followed by predicting the mutation effect on energy stability; the most damaging mutations were chosen for additional investigation by Mutation3D, Project hope, ConSurf, BioEdit, and UCSF Chimera tools. Results: A total of 5 mutations out of 248 were likely to be responsible for the structural and functional variations in CEBPA protein, whereas in the 3′-untranslated region (3′-UTR) the result showed that among 350 SNPs in the 3′-UTR of CEBPA gene, about 11 SNPs were predicted. Among these 11 SNPs, 65 alleles disrupted a conserved miRNA site and 22 derived alleles created a new site of miRNA. Conclusions: In this study, the impact of functional mutations in the CEBPA gene was investigated through different bioinformatics analysis techniques, which determined that R339W, R288P, N292S, N292T, and D63N are pathogenic mutations that have a possible functional and structural influence, therefore, could be used as genetic biomarkers and may assist in genetic studies with a special consideration of the large heterogeneity of AML.


Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2725-2725
Author(s):  
Sayantanee Dutta ◽  
Gudrun Pregartner ◽  
Frank G. Rücker ◽  
Ellen Heitzer ◽  
Armin Zebisch ◽  
...  

In more than 50% of human cancers, somatically acquired aberrations of the tumor suppressor gene TP53 are encountered. Approx. 10% of patients with acute myeloid leukemia (AML) reveal TP53 mutations with higher incidences in therapy-related subtypes and erythroleukemias. These mutations are regarded early events of leukemogenesis. In contrast to mere deletions at the TP53 locus, TP53 mutations confer an exceedingly adverse prognosis in AML even when occurring at a subclonal level. However whether different TP53 mutations in AML exhibit a different functional impact on disease progression or outcome remains unknown. In the present study, we have investigated this issue using four TP53 specific, functional scoring systems in a large cohort of patients of the German-Austrian AML study group (AMLSG). The AMLSG cohort consisted of a total of 1537 patients with newly diagnosed AML who were intensively treated within three multicenter, clinical trials. A total of 108 TP53 mutations were detected in 98 patients using targeted amplicon sequencing - 88 (81.4%) missense, 8 (7.4%) nonsense and 6 (5.6%) splice site mutations as well as 6 small insertions and deletions. For each of the four functional TP53 scores, we have assessed their impact on overall survival (OS) and event-free survival (EFS). First, we compared the impact of TP53 missense mutations in 84 patients with all other types of mutations (n= 14). In a next approach, TP53 mutations were grouped into disruptive (n=42) and non-disruptive (n=56) ones, based on the impact of the particular mutations on the protein structure predicted from the crystal structure of p53-DNA complexes (Poeta et al. New Engl J Med 2007). We then classified missense TP53 mutations (n=84) based on their "Evolutionary Action Scores (EAp53)" (Neskey et al. Cancer Res 2015). This algorithm takes evolutionary sensitivity and amino acid conservation into account and scores missense TP53 mutations from 0 to 100. Mutations with the high EAp53 score are considered high risk whereas wild type TP53 has an EAp53 score of zero. We extracted the EAp53 score of those AMLSG patients showing missense mutations from the respective server (http://mammoth.bcm.tmc.edu/EAp53) and used the threshold of 75 from the initial publication to divide the patients into low-risk (<75, n=49) and high-risk groups (≥75, n=35). However, with these three functional scoring systems, no difference regarding OS and EFS could be shown between the mutational groups. The "Relative Fitness Score (RFS)" was recently developed for the TP53 DNA binding domain (DBD) mutants as an indicator of their functional impact (Kotlar et al. Molecular Cell 2018). A catalogue of 9833 TP53 DBD mutants were generated and their selective growth was assessed in p53 null cancer cell lines. The RFS score for each mutant is the median of its relative enrichment or depletion in culture, calculated at 3 time points and depicted as a log (base 2) value. A high RFS indicates selective growth of the mutant corresponding to its higher fitness. We extracted the RFS for the TP53 DBD mutations of the AMLSG cohort (n=83) using the online data resource (GSE115072) and performed a receiver-operating characteristics (ROC) analysis to calculate the optimal threshold of RFS separating deceased from survivors most efficiently. Thereby, the best RFS cut-off value according to the Youden index was -0.135. Applying this threshold (low-risk RFS ≤ -0.135, n=25; high-risk RFS > -0.135, n= 58) we demonstrated a significantly better OS (P=0.009) and EFS (P=0.037) for patients with a low-risk RFS in multivariable analyses adjusting for age, white blood cell count, cytogenetics and type of AML. Using the AML-specific TP53 RFS score, we could show that more than 30% of patients with TP53 mutations (25/83) reveal a significantly better survival indicating that this score is of prognostic value. Based on these findings, we propose that - along with clinical parameters - RFS values of TP53 mutations should also be considered for a comprehensive risk assessment of TP53 mutated AML patients. Disclosures Zebisch: Celgene: Honoraria; Novartis: Honoraria, Other: Advisory board; AbbVie: Other: Advisory board; Roche: Honoraria. Bullinger:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Gilead: Honoraria; Hexal: Honoraria; Menarini: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria; Bayer: Other: Financing of scientific research; Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Döhner:Daiichi: Honoraria; Jazz: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria; CTI Biopharma: Consultancy, Honoraria. Sill:Novartis: Other: Advisory board; AbbVie: Other: Advisory board; Astellas: Other: Advisory board; Astex: Other: Advisory board.


Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3374-3374
Author(s):  
Claudia Lucia Sossa ◽  
Virginia Abello ◽  
Angela María Peña ◽  
Luis Antonio Salazar ◽  
Guillermo Quintero Vega ◽  
...  

Abstract Introduction: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, accounting for almost 80 percent of the cases. Incidence of AML increases with age and it ranges from 3 to 5 cases per 100,000 persons in the United States. Advances in treatment have led to significant improvements in outcomes for younger patients, while prognosis in the elderly remains poor. There are different sociodemographic and clinical factors that have an impact on survival such as type of leukemia (secondary vs novo), low socioeconomic status, age, gender, health regimen, co-morbidities and performance status Objective: The aim of the study was to describe the impact of sociodemographic and clinical factors on survival of patients with AML in 11 health institutions from Colombia, from 2009 to June 2021. Methods: Population based on RENEHOC (online platform) and PETHEMA (Spanish Program for Hematology Treatments). Kaplan-Meier analysis was used to assess overall survival (OS) and Relapse-Free Survival global (RFS) of the different evaluated factors. Results: A total of 463 patients were included. The median age at diagnosis was 61 years (range, 19-90) and 50.5% were female. According to the FAB classification, 95 (26.6%), 84 (23.6%), and 53 (14.9%) of patients were classified as M2, M0 and M1, respectively. The cytogenetic risk was applied for 227 patients (57%), 135 (59.5%) were intermediate and 78 (34.4%) were high-risk. Secondary AML were 73 (18.2%) and these cases evolved from hematological malignancies in 38 cases (80.8%), the most common were myelodysplastic syndrome (n=16; 34%) and chronic myeloid leukemia (n=7; 50%). For induction therapy, 232 (59.7%) patients received 7+3 (cytarabine/idarubicin), 47 (11.7%) received Azacitidine (AZA) and 23 (5.7%) received FLUGA (Fludarabine/cytarabine low doses). Complete remission (CR) after induction was achieved in 53% of patients, 12% had partial remission, 20.3% had primary refractory AML. Twelve percent died during induction. The most common consolidation regimen was high dose cytarabine (HiDAC), 143 (35,6%) and 36 (9%) of patients received 1 and 2 cycles respectively. Seventy-two (51%) patients that achieved a CR relapsed, and 46 (69.7%) received second line therapy. The most common treatment was FLAG-IDA (27%), followed by best supportive care (23.8%). The response rate was 40% (CR:31.1%/PR:8.9%) with 16 (36.6%) patients being refractory to treatment. Five (11.1%) died during salvage therapy. Thirty-eight (21%) patients had a hematopoietic stem cell transplantation (HCT), 35 (92%) had allogeneic HCT and 3 (8%) autologous HCT, respectively. The median and 5-year OS for the whole population was 19 months and 27.6% (95%CI,19.7- 36.0). The median and 5-year RFS was 14 months and 21.8% (95%CI, 15.2 - 29.2), respectively (Figure 1). Sociodemographic and clinical factors such as age, ECOG PS, co-morbidies (Hypertension, diabetes, and chronic heart failure), AML subtype and leukocytosis at diagnosis were prognostic (Table 1). Conclusion: This is the first multicenter report analyzing real world data from AML patients in Colombia. Results confirm the impact of clinical factors: age, ECOG, secondary LMA on OS and RFS. Challenges includes low alloHSCT rate and low access to complete cytogenetic and molecular classification at diagnosis. Figure 1 Figure 1. Disclosures Sossa: Amgen: Research Funding. Abello: Dr Reddy's: Research Funding; Janssen: Honoraria; Amgen: Honoraria. Peña: Amgen: Research Funding. Salazar: Amgen: Research Funding. Sandoval-Sus: SeaGen, Janssen, MassiveBio, TG: Other: Advisory Board; BMS: Other: Advisory Board, Speakers Bureau. Montesinos: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Agios: Consultancy; Tolero Pharmaceutical: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Glycomimetics: Consultancy; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Stemline/Menarini: Consultancy.


Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.


2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Andoni Garitano-Trojaola ◽  
Ana Sancho ◽  
Ralph Götz ◽  
Patrick Eiring ◽  
Susanne Walz ◽  
...  

AbstractThe presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD + AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD + AML.


2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Xiang Zhang ◽  
Xuewu Zhang ◽  
Xia Li ◽  
Yunfei Lv ◽  
Yanan Zhu ◽  
...  

Abstract IKZF1 belongs to the IKAROS family of transcription factors, and its deletion/mutation frequently affects acute lymphoblastic leukemia. In acute myeloid leukemia, IKZF1 deletion has been demonstrated recurrent, but whether IKZF1 mutation also exists in AML remained largely unknown. Herein, we analyzed the IKZF1 mutation in AML. In our cohort, the frequency of IKZF1 mutation was 2.6% (5/193), and 5 frameshift/nonsense mutations as well as 2 missense mutations were identified in total. Molecularly, IKZF1 mutation was absent in fusion gene-positive AML, but it was demonstrated as the significant concomitant genetic alteration with SF3B1 or bi-alleleCEBPA mutation in AML. Clinically, two IKZF1, PTPN11 and SF3B1-mutated AML patients exhibited one aggressive clinical course and showed primary resistant to chemotherapy. Furthermore, we confirmed the recurrent IKZF1 mutation in AML with cBioPortal tool from OHSU, TCGA and TARGET studies. Interestingly, OHSU study also showed that SF3B1 mutation was the significant concomitant genetic alteration with IKZF1 mutation, indicating their strong synergy in leukemogenesis. In conclusion, IKZF1 mutation recurrently affected AML.


Blood ◽  
2011 ◽  
Vol 118 (5) ◽  
pp. 1402-1412 ◽  
Author(s):  
Ahmet H. Elmaagacli ◽  
Nina K. Steckel ◽  
Michael Koldehoff ◽  
Yael Hegerfeldt ◽  
Rudolf Trenschel ◽  
...  

Abstract The impact of early human cytomegalovirus (HCMV) replication on leukemic recurrence was evaluated in 266 consecutive adult (median age, 47 years; range, 18-73 years) acute myeloid leukemia patients, who underwent allogeneic stem cell transplantation (alloSCT) from 10 of 10 high-resolution human leukocyte Ag-identical unrelated (n = 148) or sibling (n = 118) donors. A total of 63% of patients (n = 167) were at risk for HCMV reactivation by patient and donor pretransplantation HCMV serostatus. In 77 patients, first HCMV replication as detected by pp65-antigenemia assay developed at a median of 46 days (range, 25-108 days) after alloSCT. Taking all relevant competing risk factors into account, the cumulative incidence of hematologic relapse at 10 years after alloSCT was 42% (95% confidence interval [CI], 35%-51%) in patients without opposed to 9% (95% CI, 4%-19%) in patients with early pp65-antigenemia (P < .0001). A substantial and independent reduction of the relapse risk associated with early HCMV replication was confirmed by multivariate analysis using time-dependent covariate functions for grades II to IV acute and chronic graft-versus-host disease, and pp65-antigenemia (hazard ratio = 0.2; 95% CI, 0.1-0.4, P < .0001). This is the first report that demonstrates an independent and substantial reduction of the leukemic relapse risk after early replicative HCMV infection in a homogeneous population of adult acute myeloid leukemia patients.


Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Martin S. Tallman

Abstract The prognosis for younger adults (≤ 55–60 years) with acute myeloid leukemia (AML) has improved during the last four decades. However, there has been little progress in the treatment of older adults. This disappointing observation is important because the median age of patients with AML is about 70 years. Approximately 60%–80% of younger adults with AML achieve complete remission (CR) with the cytotoxic agents cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only 30%–40% of such patients are alive and disease-free at 5 years. Among older adults, CR is achieved in 40%–55%, but there are very few long-term survivors. Many studies have evaluated the impact of alternative doses and schedules, as well as additional cytotoxic drugs, on the prognosis for this group of patients. The outcome has not improved substantially beyond that achieved with conventional doses of an anthracycline and cytarabine followed by high-dose cytarabine consolidation. Several factors identified at diagnosis can predict outcome. The most important of these is the karyotype of the leukemic cells. Another critical factor is the presence of transmembrane transporter proteins, which confer multidrug resistance and mutations in or overexpression of specific genes such as WT1, C/EBPα, BAX, and BCL-2/BAX ratio, BAALC, EVI1, KIT and FLT3. The development of specific agents directed at gene mutations, signal transduction pathways and unique cell surface antigens provide the foundation for new therapeutic strategies. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyltransferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, FLT3 inhibitors, apoptosis inhibitors, and nucleoside analogs. All of these agents can potentially address the heterogeneous abnormalities in AML and significantly improve the outcome for patients.


2018 ◽  
Vol 19 (11) ◽  
pp. 3325 ◽  
Author(s):  
Lucille Stuani ◽  
Fabien Riols ◽  
Pierre Millard ◽  
Marie Sabatier ◽  
Aurélie Batut ◽  
...  

Background: In Acute Myeloid Leukemia (AML), a complete response to chemotherapy is usually obtained after conventional chemotherapy but overall patient survival is poor due to highly frequent relapses. As opposed to chronic myeloid leukemia, B lymphoma or multiple myeloma, AML is one of the rare malignant hemopathies the therapy of which has not significantly improved during the past 30 years despite intense research efforts. One promising approach is to determine metabolic dependencies in AML cells. Moreover, two key metabolic enzymes, isocitrate dehydrogenases (IDH1/2), are mutated in more than 15% of AML patient, reinforcing the interest in studying metabolic reprogramming, in particular in this subgroup of patients. Methods: Using a multi-omics approach combining proteomics, lipidomics, and isotopic profiling of [U-13C] glucose and [U-13C] glutamine cultures with more classical biochemical analyses, we studied the impact of the IDH1 R132H mutation in AML cells on lipid biosynthesis. Results: Global proteomic and lipidomic approaches showed a dysregulation of lipid metabolism, especially an increase of phosphatidylinositol, sphingolipids (especially few species of ceramide, sphingosine, and sphinganine), free cholesterol and monounsaturated fatty acids in IDH1 mutant cells. Isotopic profiling of fatty acids revealed that higher lipid anabolism in IDH1 mutant cells corroborated with an increase in lipogenesis fluxes. Conclusions: This integrative approach was efficient to gain insight into metabolism and dynamics of lipid species in leukemic cells. Therefore, we have determined that lipid anabolism is strongly reprogrammed in IDH1 mutant AML cells with a crucial dysregulation of fatty acid metabolism and fluxes, both being mediated by 2-HG (2-Hydroxyglutarate) production.


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