CDK6 Is a Potential Prognostic Biomarker in Acute Myeloid Leukemia
Wei LiuJin-Mou YiYi LiuCong ChenKaixuan ZhangCheng ZhouHuien ZhanLiang ZhaoStephanie MoralesXielan ZhaoHui Zeng
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Abstract:
Acute myeloid leukemia (AML) is a threatening hematological malignant disease in which new successful approaches in therapy are needed. Cyclin-dependent kinase 6 ( CDK6 ), a regulatory enzyme of the cell cycle that plays an important role in leukemogenesis and the maintenance of leukemia stem cells (LSC), has the potential to predict the prognosis of AML. By analyzing public databases, we observed that the messenger RNA (mRNA) levels of CDK6 were significantly overexpressed in AML cell lines and non-acute promyelocytic leukemia (non-APL) AML patients when compared to healthy donors. Furthermore, CDK6 expression was significantly reduced in AML patients who achieved complete remission (CR) compared to that at the time of diagnosis in our validated cohort. The expression of CDK6 was tightly correlated with peripheral blood blasts, French–American–British (FAB) subtypes, CCAAT-enhancer-binding protein α (CEBPA) mutation, and chromosomal abnormalities of t(8;21). However, the clinical significance and effects of CDK6 expression on the prognosis of non-APL AML patients remain uncertain. We found that CDK6 expression was inversely correlated with overall survival (OS) among non-APL AML patients using the Kaplan–Meier analysis. CDK6 was also found to be positively associated with genes identified to contribute to the development of leukemia, including CCND2 , DNMT3B , SOX4 , and IKZF2 , as well as being negatively associated with anticancer microRNAs, including miR-187, miR-9, miR-582, miR708, and miR-362. In summary, our study revealed that CDK6 might be a potential diagnostic and prognostic biomarker in non-APL AML patients.Keywords:
Cyclin-dependent kinase 6
CEBPA
NPM1
To evaluate the frequency of the nucleophosmin (NPM1) gene and the CCAAT/enhancer binding protein α gene (CEBPA) through polymerase chain reaction (PCR) array in pediatric patients with cytogenetically normal acute myeloid leukemia (CN-AML) and explore the clinical significances of these mutations.Between August 2009 and December 2012, 30 children (<16 years old) with newly diagnosed CN-AML were included. The clinical characteristics were analyzed in these patients. PCR combined with direct sequencing was used to detect NPM1, CEBPA gene mutations. All the data were statistically analyzed using SPSS17.0 software.The gene mutations were detected in each of the 30 patients. NPM1 mutation was positive in three patients (10%) with type A mutation, while CEBPA mutation was positive in two patients (6.7%) with double mutations (TAD, bZIP) . Besides, FLT3/ITD mutation was positive in three patients. Patients with NPM1 or FLT3/ITD had a significantly elevated diagnostic WBC count with a median diagnostic WBC count of 102.80×10(9)/L compared with 18.56×10(9)/L for the patients without mutations(t = 2.353, P = 0.043), as well as the marrow blast percentage (94.0% vs. 80.0%, t = 3.804, P = 0.002). The complete remission was achieved in all the 3 patients with NPM1 mutations and 2 patients with CEBPA mutations. All the patients with these mutations also achieved 2-year event-free survival (EFS) and 2-year overall survival (OS), while 2-year EFS and 2-year OS of the other patients were (40.1 ± 11.2)% and (51.8 ± 10.9)% (P = 0.044, 0.091, respectively).NPM1 and CEBPA mutations may indicate a favorable prognosis in pediatric CN-AML.
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Summary Older adult patients (≥60 years) with acute myeloid leukaemia ( AML ) are generally considered to be poor‐risk and there is limited information available regarding risk stratification based on molecular characterization in this age group, particularly for the double‐mutant CEBPA ( CEBPA DM ) genotype. To investigate whether a molecular favourable‐risk genotype can be identified, we investigated CEBPA , NPM1 and FLT3 status and prognostic impact in a cohort of 301 patients aged 60 years or more with intermediate‐risk cytogenetics, all treated intensively. Overall survival ( OS ) at 1 year was highest in the 12 patients (4%) that were CEBPA DM compared to the 76 (28%) with a mutant NPM1 and wild‐type FLT3 ( NPM1 MUT FLT3 WT ) genotype or all other patients (75%, 54%, 33% respectively), with median survival 15·2, 13·6 and 6·6 months, although the benefit was short‐term ( OS at 3 years 17%, 29%, 12% respectively). Combination of the CEBPA DM and NPM1 MUT FLT3 WT genotype patients defined a molecular group with favourable prognosis ( P < 0·0001 in multivariate analysis), with 57% of patients alive at 1 year compared to 33% for all other patients. Knowledge of genotype in older cytogenetically intermediate‐risk patients might influence therapy decisions.
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ObjectivesTo explore NPM1, FLT3-ITD, CEBPA, and c-kit mutations in patients with acute myeloid leukemia (AML) from Chinese population.MethodsIn this study, we retrospectively analyzed the prevalence and clinical profile of NPM1, FLT3-ITD, CEBPA, and c-kit mutations in 312 patients with de novo AML.ResultsThe frequencies of NPM1, FLT3-ITD, c-kit, and CEBPA mutations were 15.4, 14.0, 7.64, and 25.6%, respectively. The occurrence rate of NPM1 mutations increased with age in patients younger than 60 years. NPM1, c-kit, and CEBPA mutations were all associated with French-American-British subtypes. Patients with NPM1 mutations and FLT3-ITD presented with higher peripheral white blood cell counts and marrow blast percentages.ConclusionBoth this and previous studies may suggest low frequencies of NPM1 and FLT3-ITD mutations in AML patients from the Chinese population, and they may have a synergistic function in stimulating proliferation of leukemia cells.
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This study is aimed to investigate the pattern of CEBPA mutations and its clinical significance in Chinese non-M3 acute myeloid leukemia (AML) patients. The entire coding region of CEBPA gene was amplified by PCR and then sequenced in samples from 233 non-M3 AML patients. Fifty mutations were identified in 37 (15.8%) patients with eleven (4.7%) double mutated CEBPA (dmCEBPA) and twenty-six (11.1%) single mutated CEBPA (smCEBPA). dmCEBPA was exclusively observed in M1 and M2 subtypes of FAB classification (P = 0.008), whereas smCEBPA occurred in almost all subtypes (P = 0.401). Patients with dmCEBPA had significantly younger age and higher WBC counts than those with wtCEBPA (P = 0.016 and 0.043, respectively). Both dmCEBPA and smCEBPA were mainly present in cytogenetically normal patients. Patients with dmCEBPA achieved higher rate of complete (CR) than wtCEBPA patients (88% vs. 51%, P = 0.037), whereas smCEBPA and wtCEBPA groups are similar (47% vs. 51%, P = 0.810). Patients with dmCEBPA had a superior overall survival (OS) compared with patients with wtCEBPA (P = 0.033), whereas patients with smCEBPA had a similar OS as patients with wtCEBPA (P = 0.976). dmCEBPA but not smCEBPA was also associated with favorable outcome in patients with wild-type NPM1 and FLT3-ITD (NPM1(wt)FLT3-ITD(wt) ). Our data confirm that dmCEBPA but not smCEBPA is prognostically favorable in NPM1(wt)FLT3-ITD(wt) AML, and suggest that the entity AML with mutated CEBPA should be definitely designated as AML with dmCEBPA in WHO classification and smCEBPA should be excluded from the favorable risk of molecular abnormalities.
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