scholarly journals Arpp19 Promotes Myc and Cip2a Expression and Associates with Patient Relapse in Acute Myeloid Leukemia

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1774 ◽  
Author(s):  
Eleonora Mäkelä ◽  
Eliisa Löyttyniemi ◽  
Urpu Salmenniemi ◽  
Otto Kauko ◽  
Taru Varila ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Group ◽  
The Cancer Genome Atlas ◽  
Standard Chemotherapy ◽  
Group Status ◽  
Standard Patient ◽  
Phosphatase 2A ◽  
Acute Myeloid

Disease relapse from standard chemotherapy in acute myeloid leukemia (AML) is poorly understood. The importance of protein phosphatase 2A (PP2A) as an AML tumor suppressor is emerging. Therefore, here, we examined the potential role of endogenous PP2A inhibitor proteins as biomarkers predicting AML relapse in a standard patient population by using three independent patient materials: cohort1 (n = 80), cohort2 (n = 48) and The Cancer Genome Atlas Acute Myeloid Leukemia (TCGA LAML) dataset (n = 160). Out of the examined PP2A inhibitors (CIP2A, SET, PME1, ARPP19 and TIPRL), expression of ARPP19 mRNA was found to be independent of the current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p = 0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p = 0.007) and in multivariable analyses (p = 0.0001) and gave additive information to EVI1 expression and risk group status (additive effect, p = 0.005). Low ARPP19 expression was also associated with better patient outcome in the TCGA LAML cohort (p = 0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression was associated with disease activity (p = 0.034), indicating its potential usefulness as a minimal residual disease (MRD) marker. Together, these data demonstrate the oncogenic function of ARPP19 in AML and its risk group independent role in predicting AML patient relapse tendency.

scholarly journals ARPP19 promotes MYC expression and associates with patient relapse in acute myeloid leukemia

2019 ◽  
Author(s):  
Eleonora Mäkelä ◽  
Eliisa Löyttyniemi ◽  
Urpu Salmenniemi ◽  
Otto Kauko ◽  
Taru Varila ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Mrna Expression ◽  
Myeloid Leukemia ◽  
Risk Group ◽  
Standard Chemotherapy ◽  
Group Status ◽  
Phosphatase 2A ◽  
Multivariable Analyses ◽  
Pp2a Inhibitor ◽  
Acute Myeloid

AbstractDespite of extensive genetic analysis of acute myeloid leukemia (AML), we still do not understand comprehensively mechanism that promote disease relapse from standard chemotherapy. Based on recent indications for non-genomic inhibition of tumor suppressor protein phosphatase 2A (PP2A) in AML, we examined mRNA expression of PP2A inhibitor proteins in AML patient samples. Notably, out of examined PP2A inhibitor proteins, overexpression of ARPP19 mRNA was found independent of current AML risk classification. Functionally, ARPP19 promoted AML cell viability and expression of oncoproteins MYC, CDK1, and another PP2A inhibitor CIP2A. Clinically, ARPP19 mRNA expression was significantly lower at diagnosis (p=0.035) in patients whose disease did not relapse after standard chemotherapy. ARPP19 was an independent predictor for relapse both in univariable (p=0.007) and in multivariable analyses (p=0.0001); and gave additive information to EVI1 expression and risk group status (additive effect, p=0.005). Low ARPP19 expression also associated with better patient outcome in TCGA LAML cohort (p=0.019). In addition, in matched patient samples from diagnosis, remission and relapse phases, ARPP19 expression associated with disease activity (p=0.034).Together, these data identify ARPP19 as a novel oncogenic PP2A inhibitor protein in AML, and demonstrate its risk group independent role in predicting AML patient relapse tendency.

Flow Cytometry Quantification of Leukemic Stem Cells Is Associated with Risk Stratification and May Be Useful for Minimal Residual Disease in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1470-1470
Author(s):  
Lorena Lobo Figueiredo Pontes ◽  
Leandro F. Dalmazzo ◽  
Luciana Correa Oliveira de Oliveira ◽  
Bárbara A Santana-Lemos ◽  
Felipe M Furtado ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Group ◽  
Leukemic Stem Cells ◽  
The Poor ◽  
Hla Dr ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 1470 Investigation of minimal residual disease (MRD) after remission induction (RI) therapy provides important information for risk assessment in patients with acute myeloid leukemia (AML). The presence of immature and chemotherapy-resistant leukemic stem cells (LSC) within the bulk of AML blasts at diagnosis and in post-induction bone marrow (BM) may lead to relapses. Nevertheless, whether the frequency of cells with LSC characteristics and their clearance after induction is correlated with prognosis has not been established. Using four-color multiparametric flow cytometry (MFC), BM quantification of leukemic associated phenotypes (LAPs) and LSCs was performed at diagnosis and after the first RI from 37 AML patients, excluding acute promyelocytic leukemia, with a median age of 48 years and a male/female ratio of 0.95. All patients received the conventional daunorrubicin and cytarabin (3 + 7) RI chemotherapy. Complete remission (CR) was defined as BM blast count inferior to 5%. Thirty-three patients were classified according to the European Leukemia Net recommendation and 9/32 (28.1%) patients were allocated in favorable, 14/32 (43.8%) in intermediate and 9/32 (28.1%) in poor cytogenetic/molecular risk group. FLT3-ITD mutation was detected in 9/33 (27.3%) and 5/28 (17.9%) carried NPM1 mutation. MRD identification was performed on 20 erythrocyte-lysed whole BM samples after staining with a panel of directly conjugated monoclonal antibodies. Five patients were excluded from this analysis because a LAP could not be identified. Blasts gating was performed considering the low expression of CD45 and sideward scatter (SSC) and CD34 expression (these latter, when more than 20% of blasts were detected at diagnosis). Within this population, the following LAPs were investigated: CD15/CD117, HLA-DR/CD13, HLA-DR/CD33, CD2/CD56, CD19/CD11b, CD42a/CD33, CD64/CD11c or CD14/CD11c. LSCs were selected by the same CD45dim × SSC gating strategy and defined as CD34+/CD38−/CD123+. After staining procedures, at least one hundred thousand events were acquired in a FACScalibur flow cytometer and analysis was performed using the Cell Quest software. LAP and LSC quantification, at diagnosis and at days 21 to 30 of RI, was analyzed as a categorical variable defined as lower or higher than the median and was compared to the following variables: age (< or > 60 years old); WBC count (< or > 30 × 103); cytogenetic/molecular risk; and morphological CR. The comparison between LAP and LSC quantification at both time points was also assessed. Comparison of categorical variables was performed using Fisher's exact test or Yates' corrected chi-square for two or more variables, respectively. Statistical analyses were performed using SPSS 13.0 software and P < 0.05 was considered to be significant. LSC quantification at diagnosis was found at varying frequencies across different cytogenetic/molecular risk groups, being higher at the poor risk group (P = 0.041). Of note, 100% of the poor risk patients had high levels of LSC at diagnosis. In addition, the presence of FLT3-ITD mutation was associated with higher amounts of the LSC population at diagnosis (P = 0.043). The most frequent detected LAP was CD45dim/CD34+/HLA-DR+/CD13+. Low or high expression of the LAP was not correlated with the prognostic variables at diagnosis. CR rate was 83.33% and was not different in the groups with high or low levels of LSC at diagnosis. However, LAP and LSC quantification after RI were found to be correlated (P = 0.018), suggesting that the LSC subpopulation can be useful for MRD monitoring at this early treatment time-point. Therefore, LSC quantification by MFC at diagnosis can identify patients at high risk of relapse and offers the opportunity to study the stem cell compartment after chemotherapy. These findings are particularly important for the intermediate normal karyotype risk group patients, who frequently do not have specific molecular targets for MRD monitoring. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Predicting Minimal Residual Disease in Acute Myeloid Leukemia through Stochastic Modeling of Clonality

2019 ◽  
Author(s):  
Khanh Dinh ◽  
Roman Jaksik ◽  
Seth J. Corey ◽  
Marek Kimmel
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
The Cancer Genome Atlas ◽  
Current Evidence ◽  
Random Events ◽  
Time To Relapse ◽  
Minimal Residual ◽  
Acute Myeloid

AbstractEvent-free and overall survival remains poor for acute myeloid leukemia (AML). Chemo-resistant clones contributing to relapse of the disease arise from minimal residual disease (MRD) rather than resulting from newly acquired mutations during or after chemotherapy. MRD is the presence of measurable leukemic cells using non-morphologic assays. It is considered a strong predictor of relapse. The dynamics of clones comprising MRD is poorly understood and is considered influenced by a form of Darwinian selection. We propose a stochastic model based on a multitype (multi-clone) age-dependent Markov branching process to study how random events in MRD contribute to the heterogeneity in response to treatment in a cohort of six patients from The Cancer Genome Atlas database with whole genome sequencing data at two time points. Our model offers a more accurate understanding of how relapse arises and which properties allow a leukemic clone to thrive in the Darwinian competition among leukemic and normal hematopoietic clones. The model suggests a quantitative relationship between MRD and time to relapse and therefore may aid clinicians in determining when and how to implement treatment changes to postpone or prevent the time to relapse.Author summaryRelapse affects about 50% of AML patients who achieved remission after treatment, and the prognosis of relapsed AML is poor. Current evidence has shown that in many patients, mutations giving rise to relapse are already present at diagnosis and remain in small numbers in remission, defined as the minimal residual disease (MRD). We propose a mathematical model to analyze how MRD develops into relapse, and how random events in MRD may affect the patient’s fate. This work may aid clinicians in predicting the range of outcomes of chemotherapy, given mutational data at diagnosis. This can help in choosing treatment strategies that reduce the risk of relapse.

scholarly journals Detection of Measurable Residual Disease May Better Predict the Outcome Rather Than Mutations Based on Next-Generation Sequencing in Acute Myeloid Leukemia with Biallelic Mutations of CEBPA

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1449-1449
Author(s):  
Jing Wang ◽  
Hao Jiang ◽  
Xiaojun Huang ◽  
Guorui Ruan ◽  
Run-Qing Lu
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Group ◽  
Low Risk ◽  
Wild Type ◽  
Generation Sequencing ◽  
Acute Myeloid

Objectives: Acute myeloid leukemia (AML) patients with biallelic mutations of CEBPA (bi CEBPA) have a 30-50% relapse rate after standard chemotherapy. This study established the value of multiparameter flow cytometric measurable residual disease (MFC-MRD) detection, mutations based on next-generation sequencing (NGS), and compares the outcomes of risk stratification treatment in adult bi CEBPA AML patients. Methods: From March 2014 to December 2018, 124 patients with newly diagnosed acute myeloid leukemia with bi CEBPA were treated with chemotherapy. Out of these, 93 patients were analyzed further by a sensitive NGS assay for mutations in 87 candidate genes. MRD was detected in all patients by MFC after each cycle of induction and consolidation chemotherapy and every 3 months later. Results: Among these patients, 73 patients were male (58.9%), and median age was 37.5 (16-69) years. The expression of CD34, CD117, CD7, HLA-DR, CD15, CD33 and CD13 in 124 patients were 120 (96.8%), 123 (99.2%), 112 (90.3%), 107 (86.3), 93 (75.0%), 115 (92.7%) and 107 (86.3%) respectively. The most common co-occurring mutations were found in the GATA2 (n=29/93, 31%), WT1 (n=20/93, 21.7%), NRAS (n = 13/93, 14.0%), CSF3R (n = 12/93, 12.9%), and TET2 (n = 9/93, 9.6%) genes. All patients (100%) achieved complete remission (CR) including 114 patients (91.9%) who achieved it with only 1 induction course. The median follow-up was 33.5 (4-69) months. The 3-year Cumulative incidence of relapse (CIR), disease-free survival (DFS) and overall survival (OS) were 32.8%, 64.7%, and 84.3%, respectively. Univariate analysis results shown that WT1 Wild-type was favorable factor of 3-year CIR (23.3% vs. 47.0%, P=0.022) and 3-year DFS (75.5% vs 53.0%; P=0.031), GATA2 Wild-type had good trend for lower CIR and longer DFS and CSF3R Wild-type had inferior trend for higher CIR and shorter DFS. Patients with sustained positive MRD status after 2 consolidation cycles and MRD negative status loses in any time defined as "MRD high risk" had higher CIR (3-year CIR, 100% vs 25.5%; P&lt;0.001; 81.5% vs 6.4%; P&lt;0.001, respectively) and worse DFS and OS (3-year DFS, 0% vs 71.5%; P&lt;0.001; 16.8% vs 90.2%; P&lt;0.001, respectively; 3-year OS, 39.0% vs 89.8%; P&lt;0.001; 72.2% vs 96.5%; P=0.001, respectively ) than those with persistent negative MRD status that defined as "MRD low risk" (Figure). Multivariate analysis showed that MRD low risk was the only favorable factor of CIR, DFS and OS (CIR: HR=37.3, 95%CI: 8.6-161.3, P&lt;0.001;. DFS: HR=24.6, 95%CI: 7.2-84.0, P&lt;0.001; HR=28.2, 95%CI: 2.1-374.1, P=0.011; respectively). Thirty-two (91.4%) MRD high risk patients (P&lt;0.001) relapsed at a median time of 8 months (range: 3-32 months) include 21 patients of MRD negative status loses in any time and 11 patients with positive MRD status after 2 consolidation cycles. In totally 35 relapsed patients, 3 patients give up, 19 (61.3%) patients achieved CR2 after induction again. 15 CR2 and 4 non-remission patients underwent allo-HSCT achieved superior 3-year OS (83.0% vs 5.1%; p= 0.034; 75.0% vs 0%; p=0.006; respectively) than chemotherapy. To assess the role of risk stratification treatment by transplant or non-transplant, the124 patients were divided into 2 groups by the unique risk factor: MRD high risk group (n=43, 34.7%) and MRD low risk group (n=81, 65.3%). In the MRD low risk group (median follow-up: 35 months; range: 4-65 months), there was no significant difference in probabilities of 3-year OS (92.3% vs. 96.9%, P=0.428) between the transplant and non-transplant cohorts. In the MRD high risk group (median follow-up: 30 months; range: 7-69 months), 3-year OS was significantly better in the transplant cohort than in the non-transplant cohort (84.0% vs. 44.3%, p=0.007).Conclusions: MRD high risk may better predict the outcome rather than mutations based on NGS in AML with bi CEBPA, and allo-HSCT may achieve superior survival in MRD high risk patients. Key words: Acute myeloid leukemia with biallelic CEBPA mutations; next-generation sequencing; multiparameter flow cytometric measurable residual disease; allogeneic stem cell transplantation; Chemotherapy Disclosures No relevant conflicts of interest to declare.

Minimal Residual Disease Monitoring by Four Color Flow Cytometry before Second Induction Is an Independent Prognostic Factor in Childhood Acute Myeloid Leukemia - AML-BFM MRD Study Group.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 671-671
Author(s):  
Claudia Langebrake ◽  
Michael Dworzak ◽  
Ondrej Hrusak ◽  
Ester Mejstrikova ◽  
Frank Griesinger ◽  
...  
Keyword(s):  
Risk Factors ◽  
Flow Cytometry ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Risk Group ◽  
Time Points ◽  
Childhood Acute Myeloid Leukemia ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Monitoring of minimal residual disease (MRD) by flow cytometry in childhood acute myeloid leukemia (AML) is still a topic of discussion in terms of the optimal time of analysis and the best antibody combinations. Here we report the largest prospective international series of MRD monitoring (395 samples) in children with AML (n=124). All children have been treated according to the AML-BFM 98 study. Based upon a CD33/CD34 backbone, a wide panel of antibodies, independent from the initial immunophenotype, was applied at up to four defined time points during treatment (MRD1: day 15, MRD2: before 2nd induction, MRD3: before 3rd block, MRD4 before 4th block). For each of the 12 leukemia associated immunophenotypes (LAIP) and time points, a threshold level based upon a previous retrospective analysis of 149 other children with AML as well as analysis of normal bone marrow was determined. Regarding all four time points there is a statistically significant difference in the 3-year event free survival (EFS) in those children presenting with MRD positivity at ≥ 3 time points (pEFS 68% vs. 33%, p=0.01). The MRD level at time point 2 has turned out to have the most significant predictive value for 3-year EFS: 66% (n=104) vs. 35% (n=17), plogrank=0.006. Regarding the standard risk group (defined by FAB subtype [M1, M2± Auer rods, M3, M4eo], favorable cytogenetics and morphologically determined treatment response at day 15) only, it is possible to identify a subgroup with poor outcome (20% [n=5] vs. 88% [n=40], plogrank &lt;0.0001). In accordance with this, a multivariate analysis proved the MRD2 as a significant prognostic factor (pChi2=0.023) independent from the known risk factors like FAB subtype, cytogenetics or morphological blast percentage at day 15. As a conclusion, (A) MRD monitoring before second induction has the same predictve value as examining MRD level at four different time points during intensive chemotherapy and (B) the immunologic analysis of MRD before second induction is particulary suitable for risk group stratification and therapeutic consequences in addition to the known risk factors.

scholarly journals Identification and validation of obesity-related gene LEP methylation as a prognostic indicator in patients with acute myeloid leukemia

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Ting-juan Zhang ◽  
Zi-jun Xu ◽  
Yu Gu ◽  
Ji-chun Ma ◽  
Xiang-mei Wen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Indicator ◽  
The Cancer Genome Atlas ◽  
Related Gene ◽  
Targeted Bisulfite Sequencing ◽  
Specific Pcr ◽  
Frequent Event ◽  
Acute Myeloid

Abstract Background Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. Results In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. Conclusions Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.

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