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.

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.

scholarly journals Cytidine deaminase genotype and toxicity of cytosine arabinoside therapy in children with acute myeloid leukemia

2009 ◽  
Vol 144 (3) ◽  
pp. 388-394 ◽  
Author(s):  
Deepika Bhatla ◽  
Robert B. Gerbing ◽  
Todd A. Alonzo ◽  
Heather Conner ◽  
Julie A. Ross ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
Cytidine Deaminase ◽  
Acute Myeloid

BAG1 Overexpression Restrains the Anti-Apoptotic BCL2, MCL1 and HSP70 Proteins in Acute Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2492-2492
Author(s):  
Sanja Aveic ◽  
Elena Manara ◽  
Benedetta Accordi ◽  
Riccardo Masetti ◽  
Andrea Pession ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Cell Survival ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Leukemia Cell ◽  
White Blood Count ◽  
Apoptotic Pathway ◽  
Aberrant Expression ◽  
Acute Myeloid

Abstract Abstract 2492 BACKGROUND: Childhood Acute Myeloid Leukemia (AML) is a heterogeneous disease characterized by recurrent genetic aberrations; impaired apoptosis of leukemia cells can also contribute to disease development. BCL2-associated AthanoGene1 (BAG1) is a multifunctional protein preferentially supporting cell survival. Its aberrant expression was demonstrated in diverse cancer types. We previously reported high expression of BAG1 protein in leukemia cell lines. We showed that leukemic cell survival was impaired after silencing BAG1. Additionally, we confirmed that, in vitro, BAG1 acted in synergy with BCL2 and influenced MCL1 expression, both being important anti-apoptotic players in AML (Aveic et al. PlosOne 2011). AIM: We investigated BAG1 expression and role in pediatric AML samples collected at diagnosis, as well as its partner molecules BCL2, MCL1 and HSP70. We then evaluated whether BAG1 may affect patient survival. METHODS: Expression of BAG1 was studied at mRNA and protein levels, using RQ-PCR and Western Blot (WB). Initially, 10 patients with AML whose samples were collected at diagnosis and during therapy while they were in disease remission, were included. Subsequently, wide protein expression was performed by Reverse-phase protein array (RPPA) on a further cohort of 66 newly diagnosed AML patients enrolled into the AIEOP-LAM 2002 protocol. RESULTS: BAG1 mRNA resulted to be heterogeneously expressed in AML cases. Furthermore, BAG1 protein was highly expressed in leukemia samples when compared with healthy bone marrow (hbm), and with patient bm in remission, where BAG1 was undetectable by WB analysis. By RPPA, we confirmed the overexpression of BAG1 protein in 56/66 AML patients (84.8 %) with respect to hbm (113616 ± 66721 Arbitrary Unit (AU); mean fold increase: 2.36). Then, we studied its anti-apoptotic co-partner BCL2, whose expression was found to correlate with BAG1 over-expression (110033 ± 89117 AU, p<0.001). We hypothesized that high BAG1 and BCL2 expression may sustain anti-apoptotic signal in AML. We demonstrated that the active phosphorylated form of BCL2, as well as MCL1, resulted to be overexpressed in AML pediatric patients (BCL2S70 = 70387 ± 40864 AU; p<0.001; MCL1 = 112309 ± 49254 AU; p<0.001). BAG1 has a more specialized role in regulating protein degradation; such a specialized function is accomplished together with HSP70 that co-localized with BAG1 in complexes. HSP70 accumulates inside the cells after exposure to stress, promoting their survival, and, in contrast to normal cells, it is expressed abundantly in most cancers. We showed a positive correlation between HSP70 protein expression and BAG1, BCL2 and MCL1 overexpression (112420 ± 4289 AU; p<0.001). We subdivided AML patients according to BAG1 protein expression into quartiles and studied its relation with biological and clinical features. No significant correlation was found with karyotype, molecular genetics, FAB-morphology, age and white blood count. We highlighted a higher frequency of t(8;21) AML1-ETO translocated patients (who are stratified in standard risk group with a better prognosis in the AIEOP AML 2002 protocol) with low BAG1 expression [9/14 patients (64.3 %) of first quartile; p<0.001]. Studying the event-free survival through the Kaplan Meier method of patients with low (quartile 1+2) and high BAG1 expression (quartiles 3+4), we found a better outcome for patients belonging to the former group, as compared to the latter one (72 % EFS vs. 54% at 3y, p= 0.08, SR= 0.1). CONCLUSIONS: We demonstrate that BAG1 is overexpressed in the majority of childhood AML, and that this correlated with high levels of anti-apoptotic proteins such as BCL2, MCL1 and HSP70. We propose that an aberrant activation of the anti-apoptotic pathway in AML may play a crucial role in leukemia development, and it deserves further investigations. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Secondary Acute Myeloid Leukemia: Demographic, Physiopathogenic, Clinical and Therapeutic Comparative Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5096-5096
Author(s):  
Roberto Ovilla ◽  
Renee Leonor Crisp ◽  
Pamela E Baez-Islas ◽  
Jorge A Arbelbide ◽  
Sofia Grille ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Performance Status ◽  
White Blood Count ◽  
Poor Risk ◽  
Secondary Acute Myeloid Leukemia ◽  
Significant Difference ◽  
Acute Myeloid

INTRODUCTION Secondary Acute Myeloid Leukemia (s-AML) evolves from a previous hematopoietic clonal disease such as Myelodysplastic Syndromes (MDS/AML), myeloproliferative neoplasia (NPM/AML), medullary insufficiencies - aplastic anemia - (AA/AML) or exposure to chemo or radiotherapy (t-AML). The objective of this work is to describe and highlight the demographic, pathophysiologic and clinical-therapeutic characteristics of s-AML patients compared with p-AML. METHODS This is a retrospective cohort study based on the casuistry from 34 reference centers in Latin America during a period of 10 years (JAN10'-MAY19'). Patients ≥18 years old with primary AML, excluding the promyelocytic subtype (p-AML), and s-AML were admitted. Age, gender, performance status, comorbidity, cytogenetics, mutations, AML subtypes, extramedullary compromise, treatments and overall survival (OS) were analyzed. Statistically, Graph Pad Prism version 5.00 and, SPSS version 17 were used. RESULTS One thousand eleven patients with newly diagnosed AML were recruited, 693 (68.5%) corresponded to p-AML and 318 (31.5%) to s-AML. The demographic differences between p-AML and s-AML are shown on Table 1. Subtypes of s-AML: t-AML (18.5%), MDS/AML (58.2%), NMP/AML (13.5%), AA/AML (5.7%) and others s-AML (4.1%). Global median age was 58 years (R 18-93) and male 52%. Extramedullary compromise in CNS (3.2%) and other organs (5.5%). Seven hundred ninety-three cytogenetic studies were evaluable (based on MRC classification): High (22.3%), Intermediate (68.3%) and Low Risk (9.3%). FLT3 mutation was more frequently found in p-AML. In s-AML, the multivariate study showed short overall survival associated with ECOG ≥2 (HR:2.0), white blood count ≥ 50x109/L at diagnosis (HR:1.9), poor risk karyotype (HR:1.6) and age over 60 years (HR:1.5). At least, 883 patients received treatment (Table 2). During this study period, 211 patients (21%) were transplanted; 49 (23%) were s-AML; histoidentical related donor (46%), haploidentical (39%), non-related (8%) and autologous (7%). The median survival for all AML was 11.0 months with a statistically significant difference in favor of the p-AML (Figure 1). CONCLUSION Performance status (by ECOG ≥2), age ≥60, level of leukocytes a ≥50x109/L, poor risk karyotype and s-AML subtype at diagnosis had a significant worse impact on overall survival. Most patients with s-AML came from MDS, they were older and their incidence increased as the population aged. They presented more comorbidities and worse performance status. Undoubtedly, our findings showed that s-AML is a distinct high risk subset of myeloid disorder with adverse prognosis and represents a therapeutic challenge. Disclosures No relevant conflicts of interest to declare.

Long-term survival after induction therapy with idarubicin and cytosine arabinoside for de novo acute myeloid leukemia

2000 ◽  
Vol 79 (10) ◽  
pp. 533-542 ◽  
Author(s):  
M. Flasshove ◽  
P. Meusers ◽  
J. Schütte ◽  
R. Noppeney ◽  
D. W. Beelen ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Cytosine Arabinoside ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Term Survival ◽  
Long Term Survival ◽  
Acute Myeloid

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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