The Activator of Transcription 3 (STAT3) Gene Polymorphisms Are Associated with Treatment Outcomes In Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4858-4858
Author(s):  
Bao-An Chen ◽  
Yue-jiao Zhong ◽  
Ji-feng Feng ◽  
Lu Cheng ◽  
Yufeng Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Chinese Population ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Strong Relationship ◽  
Cellular Transformation ◽  
Janus Kinase ◽  
Nucleotide Polymorphisms ◽  
Free Survival ◽  
Acute Myeloid

Abstract Abstract 4858 Objectives: In the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway signaling pathway, the STAT3 is one of the most prominent predictable factors for cancer and leukemia. STAT3 activation might promote cellular transformation and therefore have an important role in human tumors. This study was aimed to investigate the relationship between the STAT3 polymorphisms and the treatment responses of AML in the Chinese population. Methods: We tested three single nucleotide polymorphisms (SNPs) with 130 Acute Myeloid Leukemia (AML) patients. Genomic DNA was isolated from peripheral blood and assayed by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF). Results: The results showed there were strong relationship between unfavorable cytogenetic, partial remission (even no remission) and the frequencies of GG genotype in rs9909659 (P=0.01 and 0.03) and the patients less than 45 years old was significant association with GA/AA genotype (P=0.01). But associations were not confirmed about event-free survival and leukemia-free survival in the Chinese population studied. Conclusions: It is clear that the AML patients with GG genotype in rs9909659 are not sensitive to standard chemotherapy method Disclosures: No relevant conflicts of interest to declare.

Association of Polymorphisms of Cytosine Arabinoside- Metabolizing Enzyme Gene with Therapy Efficacy for Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4328-4328
Author(s):  
Peipei Xu ◽  
Baoan Chen ◽  
Ran Liu ◽  
Jifeng Feng ◽  
Lu Cheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cytosine Arabinoside ◽  
Chinese Population ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Cytidine Deaminase ◽  
White Blood Count ◽  
Chemotherapy Response ◽  
Nucleotide Polymorphisms ◽  
Acute Myeloid

Abstract Abstract 4328 Background The cytosine arabinoside (Ara-C)-based chemotherapy is the major remedial measure for acute myeloid leukemia (AML). Deoxycytidine kinase (DCK) and cytidine deaminase (CDA) are the key enzymes in the metabolism of Ara-C. Many single nucleotide polymorphisms (SNPs) and haplotypes of DCK and CDA, which contribute to susceptibility to Ara-C, have been identified in Africans and Europeans. However, there has been no report about the relation among three SNPs in DCK (rs115543896, rs72552079, and rs111454937) and two SNPs in CDA (rs2072671 and rs60369023), and their clinical response to Ara-C for a Chinese population. In this study, we aimed to investigate whether these five SNPs are associated with the therapeutic outcomes of Ara-C-based chemotherapy regimens in patients with AML. Methods A total of 151 patients with AML in a Chinese population were enrolled in our study. SNPs genotyping were performed using the MassARRAY system (Sequenom) by means of the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) method. Results The results illustrated that DCKrs111454937 AA genotype was more frequent in patients with higher platelet count, and A allele frequency was significantly higher in the group £40 years, lower white blood count (WBC) patients group and the group with platelet counts >60′109/L. Meanwhile, both DCKrs72552079 TC (OR=1.225, 95% CI=1.225–9.851, P=0.0192) and CDArs60369023 GA (OR=9.851, 95% CI=1.31–77.93, P=0.0263) significantly improved Ara-C-based chemotherapy response. While DCKrs11554389 AA (OR=0.147, 95% CI=0.027–0.801, P=0.0267) was associated with the decrease of Ara-C-based chemotherapy response. Conclusion It is evident that the DCK and CDA polymorphisms might be the important markers for the AML patients' therapy outcomes in a Chinese population. Disclosures: No relevant conflicts of interest to declare.

Fludarabine, Cytarabine, and Attenuated-Dose Idarubicin (m-FLAI) Induction for Elderly Patients with Acute Myeloid Leukemia: Results of a Multicenter Phase II Study,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3626-3626
Author(s):  
Yoojoo Lim ◽  
Youngil Koh ◽  
Sung-Soo Yoon ◽  
Seonyang Park ◽  
Byoung Kook Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
Free Survival ◽  
Induction Regimen ◽  
Acute Myeloid

Abstract Abstract 3626 Introduction: Although there have been remarkable improvements in treatment of acute myeloid leukemia (AML), the prognosis of AML in elderly patients remains poor, and the best induction chemotherapy for these patients remains yet unknown. To devise an effective induction regimen for elderly patients with AML, we conducted a phase II trial to evaluate the efficacy and safety of the modified fludarabine, cytarabine, and attenuated-dose idarubicin (m-FLAI) regimen in these patients. Patients and Methods: Elderly (60 years or older) AML patients who did not receive previous chemotherapy were enrolled. Patients received two consecutive cycles of m-FLAI chemotherapy as an induction. The m-FLAI regimen was comprised of fludarabine (25mg/m2, days 1–4), cytarabine (1000mg/m2, days 1–4), and attenuated-dose idarubicin (5mg/m2, days 1–3). The primary end point was complete remission (CR) rate. Results: A total of 108 patients (median age 68.4 years, M:F=64:44) were enrolled. CR was achieved in 62.9% of patients, and treatment-related mortality rate (TRM) was 25.8%. Median overall survival (OS) was 9.3 months, and median event-free survival (EFS) was 6.6 months. The mortality at 30 and 60 days was 18% and 24%, respectively. Performance status and comorbidity did not have prognostic value in these patients. Bone marrow expression of CD117 was related to long EFS and OS. Conclusion: In conclusion, m-FLAI is a safe and effective induction regimen for previously untreated AML in elderly patients. Bone marrow CD117 expression is an independent good prognostic factor in these patients. (ClinicalTrials.gov number, NCT01247493) Disclosures: No relevant conflicts of interest to declare.

Nonanthracycline Induction Chemotherapy (T-FLAG) for Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4356-4356
Author(s):  
Amit Mahipal ◽  
Emmanuel C. Besa ◽  
Anne Marie Valorie-Oberlie ◽  
Isaac Matthias ◽  
Adam Thode
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Progression Free Survival ◽  
Free Survival ◽  
Related Mortality ◽  
Acute Myeloid

Abstract Abstract 4356 Introduction: Prognosis of elderly patients (age>60 years) with acute myeloid leukemia (AML) is poor as compared to younger patients with a higher incidence of cardiac co-morbidities. With standard induction therapy, complete remission (CR) is achieved in 35% to 50% of elderly patients. However, the induction anthracycline containing chemotherapy related mortality is in this population has been reported to be approximately 30%. We attempted to decrease this by replacing the anthracycline with topotecan. Alternative therapies are needed that are less toxic but equally efficacious. In a phase I/II trial of the combination of topotecan, fludarabine, cytarabine and G-CSF (T-FLAG) in elderly AML and MDS, there was 50% CR and 15% treatment related deaths. In this study, we report patients >60 years of age treated with T-FLAG as an initial therapy for AML at our institute. Methods: We retrospectively reviewed the charts of elderly patients with AML treated with T-FLAG at our institution. Elderly patients were defined as more than 60 years of age. IRB approval was obtained for the study. All patients received topotecan 2mg/m2, fludarabine 30 mg/m2, and cytarabine 2000 mg/m2 all given over 30 min from day 1 to day 4 and G-CSF 400 μ g/m2/day from the day 5 to neutrophil counts recovery. International working group criteria was used to assess responses. All statistical analysis was done using SAS statistical software. Descriptive statistics were used. Progression free survival was defined from the time of diagnosis to progression, death or last follow up, whichever comes first. Overall survival and progression free survival was calculated using Kaplan and Meier method. Results: Thirteen elderly patients were treated with T-FLAG. The median age of diagnosis was 73 years (Range: 60–86 years). There were 10 male and 3 female patients. Ten (77%) patients had complex cytogenetics. Cardiomyopathy (EF <50%) or elevated liver function tests precluding anthracycline use was present in 54% of the patients. Response rate was 69% with 7 (54%) patients achieving CR and 2 (15%) patients achieving partial remission. Out of 10 patients with abnormal cytogenetics at baseline, 7 (70%) patients had cytogenetic CR. Eleven (85%) patients were alive at day 30. Median progression free survival and overall survival was 36 weeks and 54 weeks respectively. The median time for the recovery of neutrophil counts (>500/μ L) was 22 days (Range: 10–47 days). Conclusions: In this study of unfavorable risk group elderly patients, T-FLAG induction chemotherapy results in comparable remission rates with low induction chemotherapy related mortality. It may be an alternative regimen for elderly patients with complex cytogenetics or patients who cannot tolerate anthracyclines. More studies are needed to confirm these results. This however, may be useful to bridge patients to transplant or maintenance demethylating agents to improve survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Comparable Leukemia-Free Survival after Autologous Hematopoietic Cell Transplantation Versus HLA-Identical Sibling Hematopoietic Cell Transplantation for Adult Acute Myeloid Leukemia in First Complete Remission: A Registry Study By the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2514-2514
Author(s):  
Motonori Mizutani ◽  
Masahiko Hara ◽  
Hiroyuki Fujita ◽  
Jun Aoki ◽  
Heiwa Kanamori ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Conflicts Of Interest ◽  
Hematopoietic Cell ◽  
Free Survival ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Allogeneic hematopoietic cell transplantation (HCT) from a matched sibling donor (MSD) may provide a cure for acute myeloid leukemia in first complete remission (AML/CR1), although the procedure is associated with a higher rate of treatment-related mortality (TRM) than autologous HCT, and it remains uncertain which modality is preferable as post-remission treatment. We therefore conducted a retrospective registry-based analysis to compare the outcomes of patients with AML/CR1 receiving autologous peripheral blood (PB) grafts (n=398, median age: 47, range: 17-80) and those receiving allogeneic MSD bone marrow (BM) grafts (n=633, median age: 38, range: 16-73) or allogeneic MSD PB grafts (n=475, median age: 42, range: 16-74) between 1995 and 2011. Consequently, the 5-year overall survival (OS) rates for the autologous PB, allogeneic BM and allogeneic PB recipients were 62% (95% confidence interval [CI], 57-67%), 61% (95% CI, 57-65%; P=0.90) and 54% (95% CI, 49-59%; P=0.07), respectively (Fig. 1-A), and the 5-year leukemia-free survival (LFS) rates were 57% (95% CI, 52-62%), 58% (95% CI, 54-63%; P=0.49) and 51% (95% CI, 46-56%; P=0.12), respectively(Fig. 1-B). Meanwhile, the 5-year cumulative incidence of TRM was 8% (95% CI, 5-11%), 16% (95% CI, 13-19%; P=0.009) and 19% (95% CI, 15-23%; P=0.0001), respectively, while that of relapse was 35% (95% CI, 30-40%), 26% (95% CI, 22-29%; P=0.003) and 30% (95% CI, 26-35%; P=0.08), respectively. A multivariate analysis performed with autologous PB HCT as the reference showed a hazard ratio (HR) for OS of 0.93 (95% CI, 0.73-1.18; P=0.53) for allogeneic BM HCT and 1.08 (95% CI, 0.83-1.39; P=0.57) for allogeneic PB HCT and an HR for LFS of 0.86 (95% CI, 0.69-1.09; P=0.21) and 0.98 (95% CI, 0.77-1.24; P=0.85), respectively. Stratifying the patients according to cytogenetics (favorable, intermediate and poor) and age (<50 years and ≥ 50 years) did not influence the results. Accordingly, autologous PB HCT may be a viable alternative as post-remission therapy in patients with AML/CR1 in the absence of MSD. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Mir-130a Is Aberrantly Overexpressed in Adult Acute Myeloid Leukemia with t(8;21) and Its Suppression Induces AML Cell Death

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5096-5096 ◽  
Author(s):  
Haiping Dai ◽  
Chao Ding ◽  
Suning Chen ◽  
Roderick A. F. MacLeod ◽  
Stefan Ehrentraut ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Conflicts Of Interest ◽  
Luciferase Reporter ◽  
Event Free Survival ◽  
Free Survival ◽  
Mutational Status ◽  
Gene Assay ◽  
Acute Myeloid

Abstract Emerging evidence has revealed that miRNAs can function as oncogenes or tumor suppressor genes in leukemia. By profiling miRNA expression across a cohort (n=156) with de novo acute myeloid leukemia (AML), we identified miR-130a as significantly overexpressed in AML with t(8;21). Expression of miR-130a decreased significantly once patients with t(8;21) achieved complete remission, but increased sharply at the time of relapse. In patients with t(8;21) AML, KIT mutational status was associated with miR-130a expression - with higher expression associated with KIT activating mutations. Increased miR-130a expression in t(8;21) AML was associated with worse event-free survival, however no impact on overall survival was observed. Knockdown of RUNX1/RUNX1T1 (AML1/ETO) protein in the SKNO-1 cell line resulted in decrease of expression of miR-130a. Direct binding of RUNX1/RUNX1T1 fusion protein with the promoter sequence of miR-130a was detected with luciferase reporter gene assay. Following miR-130a knockdown, SKNO-1 demonstrated increased sensitivity to etoposide. Taken together, our data suggest that miR-130a is directly activated by RUNX1/RUNX1T1, and can be used to predict leukemia burden, event-free survival and chemotherapy sensitivity in AML with t(8;21). Disclosures No relevant conflicts of interest to declare.

Dexrazoxane Does Not Negatively Impact Survival Outcomes in Children and Young Adults with Acute Myeloid Leukemia (AML)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4886-4886
Author(s):  
Nathan J. Schloemer ◽  
Molly M. Brickler ◽  
Vanessa C. McFadden ◽  
Yumei Cao ◽  
Raymond G. Hoffmann ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Young Adults ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Free Survival ◽  
Number Of Patients ◽  
Significant Difference ◽  
Late Morbidity ◽  
Children And Young Adults ◽  
Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) comprises 5% of pediatric cancers and reports 5 year event free survival (EFS) of approximately 50% and overall survival (OS) of 60-70% following intensive multi-agent chemotherapy. Anthracyclines have been the cornerstone in upfront treatment of AML since the 1960's and continue to be used today in upfront trials for AML. Anthracycline induced cardiotoxicity remains a significant contributor to late morbidity/mortality in children and young adults with AML. The cardioprotectant dexrazoxane (Zinecard) can be used as prophylaxis to diminish the risk for cardiomyopathy but whether it affects the risk of relapse in pediatric AML is unproven. Our institution adopted the use of dexrazoxane prior to administration of any non-liposomal anthracycline for all patients in 2011. We are therefore reporting the differences in cardiac and treatment outcomes in children and young adults with AML treated with and without dexrazoxane from 2008 to 2013. Methods: We performed a retrospective chart review of children ages 0 to 21 years who received their therapy for AML at the Children's Hospital of Wisconsin (CHW) between January 1, 2008 and December 31, 2013. This study was approved by the CHW institutional review board prior to our data collection. Descriptive statistics were used to describe the study population. Echocardiogram statistics were generated with each model based on the least squares means and then transformed back to its original unit. A log rank test was used to detect differences between populations. Based on number of patients, a hazard ratio of 3 will achieve 85% power to detect a significant difference between groups. Results: Forty-four patients with AML were treated at CHW during 2008 - 2013 with 28 (64%) receiving dexrazoxane cardioprotectant and 16 (36%) did not. The median age at diagnosis was 8.1 years (5 months - 21.7 years) and 55% (n=24) were female. Six (14%) patients underwent transplantation in first complete remission and 6 (14%) underwent transplantation following relapse. No patients had history of cardiac disease, cardiac surgery or hypertension prior to treatment. We identified no statistical difference in relapse free survival (RFS) p>0.40), EFS (p>0.48) or OS (p>0.53) between groups. However, there was a significant decrease in the ejection fraction (EF %) (p=0.0018) and a significant decrease in shortening fraction (SF %) (p=0.0108) trends over time in the non-dexrazoxane group compared to patients who received dexrazoxane (Figures 1 & 2). Conclusion: Utilization of the cardioprotectant dexrazoxane prior to anthracycline chemotherapy in pediatric patients with AML demonstrated no significant difference in RFS or OS relative to our institutional controls and appeared to improve cardiac function. Further studies are needed to confirm these findings. Disclosures No relevant conflicts of interest to declare.

HLA-Mismatched Microtransplantation Vs HLA-Matched Nonmyeloablative Transplantation for Acute Myeloid Leukemia in Intermediate-Risk: Comparable Survival but Avoids of Gvhd

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 156-156 ◽  
Author(s):  
Mei Guo ◽  
Chang-Lin Yu ◽  
Zheng Dong ◽  
Kaixun Hu ◽  
Qiyun SUN ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Free Survival ◽  
Nonmyeloablative Stem Cell Transplantation ◽  
Gvhd Prophylaxis ◽  
To Receive ◽  
Acute Myeloid

Abstract The optimal therapy for intermediate-risk patients with acute myeloid leukemia (AML) in first complete remission (CR1) is uncertain. Recent studies shown that microtransplantation (MST) can improve survival in AML-CR1 patients. However, a comparison study between the MST and nonmyeloablative stem cell transplantation (NST) is lacking. 156 intermediate-risk AML-CR1 patients aged 9 to 59 years were enrolled in this study. 57 patients who had a HLA-identical donors were assigned to receive NST therapy with graft-versus-host disease (GVHD) prophylaxis. The other 99 who had no HLA-identical donors including 86 family-related, 9 distantly related and 4 unrelated donor were assigned to receive MST therapy but without GVHD prophylaxis. The probabilities of 10-year overall survival and leukemia-free survival was comparable in the MST-group and NST-group (70.7% vs. 61.4% and 59.6% vs. 57.9%). The NST-group exhibited a higher full donor chimerism (96.5%) and higher GVHD (33.3%), whereas the MST-group produced a higher donor microchimerism (75%), slightly higher relapse (32.3% vs. 22.8%) and significantly lower non-relapse mortality (6.9% vs. 19.3%, P=0.021) but without GVHD. In the MST-group, the patients with increase of WT1+ CD8+ T cells exhibited significantly higher leukemia-free survival and lower relapse than those without (92.0% vs. 40.0%, P=0.003; 8.0% vs. 50%, P=0.009). These results indicate that, compared to NST, MST produced a comparable survival, less transplantation-related mortality, avoidance of clinical GVHD and overcome limitations of HLA-barrier, suggesting a much safe and effective therapy for intermediate-risk AML-CR1, particularly for those without a HLA-identical donor. Disclosures No relevant conflicts of interest to declare.

Prognostic Impact of MLL Partial Tandem Duplication in Acute Myeloid Leukemia of Intermediate Cytogenetic Risk: A Subgroup Analysis of Cetlam Protocol 2003 & 2012

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2514-2514
Author(s):  
Marta Pratcorona ◽  
Ana Garrido ◽  
Salut Brunet ◽  
Jordi Esteve ◽  
María Camino Estivill ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Complete Response ◽  
Prognostic Impact ◽  
Free Survival ◽  
Molecular Alterations ◽  
Tandem Duplications ◽  
Acute Myeloid

Abstract Background Cytogenetics at diagnosis is the most important prognostic factor in acute myeloid leukemia (AML). Of note, intermediate cytogenetic risk group (IR-AML) is a very heterogeneous subset including normal karyotypes and all the cytogenetic abnormalities not included in the favorable or the adverse groups. Molecular alterations affecting NPM1, FLT3 and CEBPA show a prognostic impact in IR-AML. MLL partial tandem duplications (MLL-PTD) have also been described in this group of AML, but their prognostic impact have not been well established. Aim To analyze the prognostic relevance of MLL-PTD in the subset of patients diagnosed with IR-AML since 2003, and included in the CETLAM protocols LMA-2003 and LMA-2012. Methods Between 2003 and 2004 MLL-PTD were analyzed by Southern Blot (enzymes employed BglII, EcoRI, BamHI). Since 2004, a long PCR strategy was used to identify this abnormality. Results NPM1 mutations (NPM1mut), FLT3 internal tandem duplications (FLT3-ITD) and MLL-PTD were available for 893 patients. No MLL-PTD was found among 111 and 161 patients of the good and poor cytogenetic risk groups, respectively. The IR-AML group included 621 patients, and 37 carried a MLL-PTD (6%), thus only this cytogenetic group of patients was analyzed. NPM1mut were found in a 41% of patients and none of them had a concomitant MLL-PTD (p<0.001). FLT3-ITD were found in a 31% of patients, and 14 patients had also an MLL-PTD. No correlation between MLL-PTD and age, leukocyte count, and percentage of blasts in bone marrow was found. There was a significant association with gender: men were more frequently mutated than women (29 vs 8; p=0.001). Regarding outcome of IR-AML, leukemia-free survival (LFS) was significantly higher for patients without MLL-PTD (5-year LFS 44±3% vs 18±8%; p<0.001), and overall survival (OS) was also better for this subgroup of patients (5-year OS 42±2% vs 20±7%; p=0.004). There were no differences in the complete response rate, but patients with MLL-PTD had a higher risk of relapse (cumulative incidence at 5 years 39 vs 74%, p=0.000151). Among patients with MLL-PTD, no differences were observed depending on the concurrence of FLT3-ITD. When only patients with NPM1 wild-type were considered, MLL-PTD maintained a significantly poor prognostic impact (36±3% vs 21±7%; p=0.009). Conclusions MLL-PTD is a genetic alteration found in a 6% of IR-AML. Patients with this abnormality have a worse LFS and OS than the rest of patients of the IR-AML group. Based on these results, patients with MLL-PTD should be considered as patients with poor cytogenetic risk AML for treatment allocation. Disclosures No relevant conflicts of interest to declare.

In Silico Identification of Novel Acute Myeloid Leukemia Associated Missense SNPs in Human CEBPA Gene

2020 ◽  
pp. 10-24
Keyword(s):  
Acute Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Gene Interaction ◽  
Nucleotide Polymorphisms ◽  
Future Perspectives ◽  
Single Nucleotide ◽  
In Silico Identification ◽  
And Function ◽  
Acute Myeloid

Single nucleotide polymorphisms (SNPs) in CEBPA gene have been found to be associated with cancer especially Acute Myeloid Leukemia (AML). Therefore, the identification of functional and structural polymorphisms in CEBPA is important to study and discover therapeutics targets and potential malfunctioning. For this purpose, several bioinformatics tools were used for the identification of disease-associated nsSNPs, which might be vital for the structure and function of CEBPA, making them extremely important. In silico tools used in this study included SIFT, PROVEAN, PolyPhen2, SNP&GO and PhD-SNP, followed by ConSurf and I-Mutant. Protein 3D modelling was carried out using I-TASSER and MODELLER v9.22, while GeneMANIA and string were used for the prediction of gene-gene interaction in this regard. From our study, we found that the L345P, R333C, R339Q, V328G, R327W, L317Q, N292S, E284A, R156W, Y108N and F82L mutations were the most crucial SNPs. Additionally, the gene-gene interaction showed the genes having correlation with CEBPA’s co-expressions and importance in several pathways. In future, these 11 mutations should be investigated while studying diseases related to CEBPA, especially for AML. Being the first of its kind, future perspectives are proposed in this study, which will help in precision medicine. Animal models are of great significance in finding out CEBPA effects in disease.

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