Clonal Heterogeneity As Detected by Metaphase Karyotyping Is an Indicator of Poor Prognosis in Acute Myeloid Leukemia

2013 ◽  
Vol 31 (31) ◽  
pp. 3898-3905 ◽  
Author(s):  
Tilmann Bochtler ◽  
Friedrich Stölzel ◽  
Christoph E. Heilig ◽  
Christina Kunz ◽  
Brigitte Mohr ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Clonal Evolution ◽  
Prognostic Significance ◽  
Genomic Diversity ◽  
Prognostic Information ◽  
Clonal Heterogeneity ◽  
Landmark Analyses ◽  
Acute Myeloid

Purpose In acute myeloid leukemia (AML), studies based on whole-genome sequencing have shown genomic diversity within leukemic clones. The aim of this study was to address clonal heterogeneity in AML based on metaphase cytogenetics. Patients and Methods This analysis included all patients enrolled onto two consecutive, prospective, randomized multicenter trials of the Study Alliance Leukemia. Patients were newly diagnosed with non-M3 AML and were fit for intensive chemotherapy. Results Cytogenetic subclones were detected in 418 (15.8%) of 2,639 patients from the whole study population and in 418 (32.8%) of 1,274 patients with aberrant karyotypes. Among those, 252 karyotypes (60.3%) displayed a defined number of distinct subclones, and 166 (39.7%) were classified as composite karyotypes. Subclone formation was particularly frequent in the cytogenetically adverse group, with subclone formation in 69.0%, 67.1%, and 64.8% of patients with complex aberrant, monosomal, and abnl(17p) karyotypes (P < .001 each). Two-subclone patterns typically followed a mother-daughter evolution, whereas for ≥ three subclones, a branched pattern prevailed. In non–core binding factor AML, subclone formation was associated with inferior event-free and overall survival and was confirmed as an independent predictor of poor prognosis in multivariate analysis. Subgroup analysis showed that subclone formation adds prognostic information particularly in the cytogenetic adverse-risk group. Allogeneic stem-cell transplantation improved the prognosis of patients with subclone karyotypes as shown in landmark analyses. Conclusion Cytogenetic subclones are frequent in AML and permit tracing of clonal evolution and architecture. They bear prognostic significance with clonal heterogeneity as an independent adverse prognostic marker in cytogenetically adverse-risk AML.

scholarly journals High Expression of PXN Predicts a Poor Prognosis in Acute myeloid leukemia

2021 ◽  
Author(s):  
xinwen zhang ◽  
Hao Xiong ◽  
Jialin Duan ◽  
Xiaomin Chen ◽  
Yang Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Receive Treatment ◽  
To Receive ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is one of the common malignant diseases of hematopoietic system. Paxillin ( PXN ) is an important part of focal adhesions (FAs), which is related to the poor prognosis of many kinds of malignant tumors. However, no research has focused on the expression of PXN in AML. We aimed to investigate the expression of PXN in AML and its prognostic significance. Methods: Using GEPIA and UALCAN database to analyze the expression of PXN in AML patients and its prognostic significance. Bone marrow samples of newly diagnosed AML patients were collected to extract RNA, and qRT-PCR was used to detect the expression of PXN . The prognosis was followed up. Chi-square test was used to analyze the relationship between PXN expression and clinical laboratory characteristics. Kaplan-Meier analysis was used to draw survival curve, and Cox regression analysis was used to analyze the independent factors affecting the prognosis of patients with AML. The co-expression genes of PXN were analyzed by LinkedOmics to explore its biological significance in AML. Results: Kaplan-Meier analysis showed that the overall survival time of AML patients was related to whether to receive treatment and PXN expression(P<0.05). COX regression analysis showed that whether to receive treatment (HR=0.227，95%CI=0.075-0.689， P =0.009) and high expression of PXN (HR=4.484，95%CI=1.449-13.889， P =0.009) were independent poor prognostic factors in patients with AML. Conclusion: PXN is highly expressed in AML patient, and high PXN expression is an indicator of poor prognosis in AML patient.

scholarly journals Multilineage Dysplasia as Assessed by Immunophenotype in Acute Myeloid Leukemia: A Prognostic Tool in a Genetically Undefined Category

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3196
Author(s):  
Francesco Mannelli ◽  
Sara Bencini ◽  
Matteo Piccini ◽  
Giacomo Gianfaldoni ◽  
Maria Ida Bonetti ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Significance ◽  
World Health ◽  
Erythroid Cell ◽  
Multiparameter Flow Cytometry ◽  
Prognostic Information ◽  
The Impact ◽  
Insight Into ◽  
Acute Myeloid

Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

Allogeneic Stem Cell Transplant in First Complete Remission Overcomes the Poor Prognosis Associated with the FLT-3 Internal Tandem Duplication in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3491-3491
Author(s):  
Maryse M. Power ◽  
Giovanna Di Sauro ◽  
Angela Brooks-Wilson ◽  
Thomas J. Nevill ◽  
Julye C. Lavoie ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Intermediate Risk ◽  
The Poor ◽  
Exon 20 ◽  
First Complete Remission ◽  
Acute Myeloid

Abstract Introduction: FLT-3 internal tandem duplications (ITD) and mutations in the nucleophosmin 1 (NPM1)gene appear to have negative and positive prognostic significance, respectively, in newly-diagnosed patients with acute myeloid leukemia (AML) treated with conventional chemotherapy. The prognostic significance of the D835 point mutation in exon 20 of FLT-3 is uncertain. In this study the relative importance of these abnormalities in predicting outcome was compared between patients receiving chemotherapy-based consolidation (chemo) or allogeneic stem cell transplantation (alloSCT) for AML in first complete remission (CR1). Methods: DNA was extracted from diagnostic blood or bone marrow from 267 AML patients aged < 60 years who achieved CR1 with induction chemotherapy and then analyzed for the presence of the ITD by PCR and NPM1 exon 12 and FLT3 exon 20 mutations by direct sequencing. Diagnostic cytogenetic abnormalities were assigned prognostic significance using Medical Research Council (MRC) UK criteria. Patients with intermediate or poor prognostic abnormalities and a sibling donor received alloSCT in CR1. If more than 1 cycle of induction therapy was necessary to achieve CR1 or poor risk cytogenetics were detected, patients without a sibling donor received unrelated donor SCT. All other patients received a minimum of one cycle of chemotherapy consolidation. Most patients received high dose cytarabine and daunorubicin induction therapy with similar consolidation. Median (range) follow-up for the entire group was 870 days (90–6003 days). Results: The overall frequency of mutations was 25%, 10% and 24% for the ITD, D835 and NPM1 mutations, respectively. On analysis of the 230 patients remaining after exclusion of acute promyelocytic leukemia (APL), ITD was significantly associated with poor disease free (DFS), event free (EFS) and overall (OS) survival. The D835 mutation was associated with poor DFS only and no effect of the NPM1 mutations could be detected. The presence of the ITD correlated with normal cytogenetics and a high presenting white cell or blast count. 92 and 138 of 230 non-APL patients received alloSCT or chemo, respectively, as consolidation in CR1.Of these 68 in the alloSCT and 95 in the chemo groups had intermediate risk cytogenetics. ITD predicted a poor EFS, DFS and OS for chemo patients regardless of the NPM1 mutation status. For ITD positive patients, relapse risk was higher with chemo in CR1 vs alloSCT (p= 0.007). Among intermediate risk cytogenetic patients 10 of 37 (27%) ITD positive vs 29 of 59 (49%) ITD negative patients are alive after chemo consolidation in CR1 (p<0.05). In the alloSCT group no significant differences in outcomes were seen comparing ITD positive and negative patients. When intermediate risk cytogenetics patients only were considered 8 of 18 (44%) vs 28 of 52 (54%) of ITD positive and negative patients, respectively, who received alloSCT are alive (p>0.5). Conclusions: FLT3 ITD predicts a poor OS following chemotherapy as consolidation for AML in CR1. In contrast the results of alloSCT in CR1 are similar for pts with and without the ITD suggesting that alloSCT can overcome the poor prognosis associated with this mutation.

BRD4 PROTAC Degradation Agent GNE-987 Inhibits Acute Myeloid Leukemia by Targeting Super Enhancers

2021 ◽  
Author(s):  
Xu Sang ◽  
Yongping Zhang ◽  
Fang Fang ◽  
Li Gao ◽  
Yanfang Tao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Xenograft Model ◽  
Rna Seq ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a common hematological malignancy in children, with poor treatment effect and poor prognosis. Recent studies have shown that bromodomain and terminal protein inhibitors are promising antitumor drugs. As a new type of BRD4 PROTAC degradation agent, GNE-987 can slow down the growth rate of a variety of tumors and cause apoptosis, which has broad clinical prospects. However, the role of GNE-987 in AML is unclear. This study aims to explore the therapeutic effect of GNE-987 in AML and its underlying mechanism.Methods: By studying public databases, the prognostic significance of BRD4 and the correlation between AML were evaluated, and the relationship between BRD4 and the overall survival rate of AML patients was also analyzed. After adding GNE-987 to the AML cell line, cell proliferation slowed down, cycle disorder, and apoptosis increased. In the cells treated with GNE-987, western-blotting was used to detect BRD2, BRD3, BRD4 and PARP proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed the function and molecular pathway of GNE-987 in processing AML. Results: Compared with healthy donors, the expression of BRD4 in children's AML samples was higher than that of healthy donors. The high expression of BRD4 indicates a poor prognosis. GNE-987 inhibits AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3 and BRD4 are consistent with the decreased expression of VHL in AML cells. Compared with JQ1 and ARV-825, GNE-987 has a lower IC50 in AML cells. In the AML xenograft model, GNE-987 significantly reduced the liver and spleen infiltration of leukemia cells, increased the survival time of mice, and caused BRD4, Ki67 dysregulation and caspase3 activation. According to the analysis of RNA-seq and ChIP-seq, GNE-987 can inhibit AML by targeting numerous super-enhancers.Conclusions: GNE-987 has strong anti-tumor activity in AML cell lines and primary child AML samples. GNE-987 works by degrading the BET protein, thereby effectively inhibiting the expression of super enhancers and related oncogenes (such as LYL1). These results indicate that GNE-987 has very broad prospects for the treatment of AML.

scholarly journals Coexistence and Prognostic Significance of EVI1 Expression and Driver Mutations in KMT2A-Rearranged Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1409-1409 ◽  
Author(s):  
Hidemasa Matsuo ◽  
Kenichi Yoshida ◽  
Kana Nakatani ◽  
Yasuhiko Kamikubo ◽  
Daisuke Tomizawa ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Adult Patients ◽  
Driver Mutations ◽  
Significant Difference ◽  
Equity Ownership ◽  
Acute Myeloid

Background: KMT2A(MLL)-rearrangements are among the most frequent chromosomal abnormalities in acute myeloid leukemia (AML) and high EVI1 expression is known as an adverse prognostic factor in this subgroup. A recent study showed driver mutations are associated with poor prognosis in pediatric KMT2A-rearranged AML, however, the relationship between EVI1 expression and driver mutations is unclear. In this study, we examined coexistence and prognostic significance of these genetic abnormalities in pediatric and adult KMT2A-rearranged AML. Patients and Methods: Forty-four pediatric KMT2A-rearranged AML samples collected in the AML-05 study, conducted by the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG), were analyzed for 338 genes by targeted sequencing. In addition, 85 adult KMT2A-rearranged AML samples in MLL Munich Leukemia Laboratory were analyzed for 16 genes (ASXL1, BRAF, CBL, CEBPA, FLT3-ITD, FLT3-TKD, IDH1, IDH2, KIT, KRAS, NPM1, NRAS, PTPN11, RUNX1, TP53 and WT1) by amplicon deep-sequencing, direct Sanger sequencing, or melting curve analysis. In both studies, EVI1 expression was measured using quantitative RT-PCR. Results and Discussion: In pediatric KMT2A-rearranged AML (n=44), among 28 patients with low EVI1 expression, 13 patients (EVI1-WT, 46.4%) had no driver mutations and 15 patients (EVI1-MT, 53.6%) had one or more driver mutations. Among 16 patients with high EVI1 expression, 2 patients (EVI1+WT, 12.5%) had no driver mutations and 14 patients (EVI1+MT, 87.5%) had one or more driver mutations. Mutations in activated signaling pathway genes (FLT3, NRAS, KRAS, PTPN11, CBL, and BRAF) were detected in most patients with EVI1-MT (12/15, 80.0%) and EVI1+MT (13/14, 93.3%). The frequency of mutations in epigenetic regulator genes (SETD2, ASXL1, ASXL2, BCOR, KDM6A, and CREBBP) was significantly higher in EVI1-MT patients (7/15, 46.7%), compared with EVI1+MT patients (1/14, 7.1%) (P=0.04). By contrast, the frequency of mutations in cohesion complex genes (STAG2 and SMC3) was significantly lower in patients with EVI1-MT patients (0/15, 0.0%), compared with EVI1+MT patients (4/14, 28.6%) (P=0.04). The frequency of mutations in transcription factor genes (WT1, MECOM, SPI1, GATA2, and RUNX1) was also lower in EVI1-MT patients (2/15, 13.3%), compared with EVI1+MT patients (5/14, 35.7%) (P=0.21). In adult patients, the frequency of ASXL1 mutations was higher in EVI1-MT patients (3/18, 18.8%), compared with EVI1+MT patients (1/29, 3.4%) (P=0.15) and those of WT1 and RUNX1 mutations were lower in EVI1-MT patients (0/18, 0.0%), compared with EVI1+MT patients (4/29, 13.8%) (P=0.28), which were compatible with the tendency in pediatric KMT2A-rearranged AML. Next, we examined the prognostic significance of EVI1 expression and driver mutations. Compared with EVI1-WT patients, EVI1-MT patients had lower event-free survival (EFS) (3-years EFS: 84.6% vs. 65.2%, P=0.24). EFS of EVI1+MT patients (3-years EFS: 30.8%) was significantly lower than that of EVI1-WT patients (P=0.001) and EVI1-MT patients (P=0.04). EFS of EVI1+WT patients (3-years EFS: 0.0%) was also lower than that of EVI1-WT patients (P=0.003) and EVI1-MT patients (P=0.09). There was no significant difference in EFS between EVI1+WT and EVI1+MT patients (P=0.88). The results of overall survival (OS) were similar except for EVI1+WT patients (n=2) (3-years OS: EVI1-WT 92.3%, EVI1-MT 70.6%, EVI1+WT 100.0%, EVI1+MT 46.6%). Multivariate analysis including EVI1 expression, driver mutations, age, white blood cell count, and KMT2A-MLLT4 fusion showed EVI1+ is an independent prognostic factor for EFS (hazard ratio (HR): 3.02, 95% confidence interval (CI): 1.08-9.48, P=0.04). There was no prognostic significance in driver mutations (HR:1.24, 95%CI: 0.39-4.74, P=0.73). As a whole, adult patients' survival data were lower, however, the tendency was similar to that of pediatric data (3-years EFS: EVI1-WT 41.7%, EVI1-MT 24.5%, EVI1+WT 9.1%, EVI1+MT 13.5%; 3-years OS: EVI1-WT 55.6%, EVI1-MT 30.7%, EVI1+WT 18.2%, EVI1+MT 36.2%). These data showed that there is an association between EVI1 expression and the pathway of driver mutations, suggesting these abnormalities may have some cooperative mechanisms in leukemogenesis. Compared with driver mutations, high EVI1 expression may have a stronger impact on poor prognosis in KMT2A-rearranged AML, however, the results should be confirmed in the larger cohort. Disclosures Ogawa: RegCell Corporation: Equity Ownership; Kan Research Laboratory, Inc.: Consultancy; ChordiaTherapeutics, Inc.: Consultancy, Equity Ownership; Dainippon-Sumitomo Pharmaceutical, Inc.: Research Funding; Asahi Genomics: Equity Ownership; Qiagen Corporation: Patents & Royalties. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Elevated Serum Exosomal miR-125b Level as a Potential Marker for Poor Prognosis in Intermediate-Risk Acute Myeloid Leukemia

2018 ◽  
Vol 140 (3) ◽  
pp. 183-192 ◽  
Author(s):  
Lijun Jiang ◽  
Taoran Deng ◽  
Di Wang ◽  
Yi Xiao
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Significance ◽  
Elevated Serum ◽  
Prognostic Indicator ◽  
Intermediate Risk ◽  
Potential Marker ◽  
Level Group ◽  
Acute Myeloid

Background: The prognostic significance of miR-125b in intermediate-risk acute myeloid leukemia has not been well investigated. The aim of the study was to reveal the relationship between the elevated exosomal miR-125b level and the poor prognosis in adult patients with this disease. Methods: A total of 154 consecutive patients with intermediate-risk acute myeloid leukemia were enrolled. Exosomes were isolated from blood specimens. The exosomal miR-125b level was determined using quantitative real-time polymerase chain reaction. Patients received standardized therapy and were followed up for 1–24 months. Details about relapse and overall death were recorded. Results: Patients were divided into the high miR-125b level group (n = 77) and the low miR-125b level group (n = 77). In the multivariate Cox proportional hazard regression model, the high miR-125b level group was separately associated with increased risks of relapse and overall death in 2 years (hazard ratio [HR] 2.84, 95% CI 1.81–4.33 and HR 2.69, 95% CI 1.87–4.52). Kaplan-Meier analysis also revealed that a high miR-125b level was related to a higher cumulative relapse and overall death rates (p < 0.001 and p < 0.001, respectively). Conclusion: Circulating exosomal miR-125b concentration might be an independent prognostic indicator in intermediate-risk acute myeloid leukemia patients. An elevated miR-125b level indicated higher risks of relapse and overall death.

scholarly journals PRICKLE1, a Wnt/PCP signaling component, is overexpressed and associated with inferior prognosis in acute myeloid leukemia

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Duanfeng Jiang ◽  
Yanjuan He ◽  
Qiuyu Mo ◽  
Enyi Liu ◽  
Xin Li ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Polarity ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Planar Cell Polarity ◽  
Expression Profiles ◽  
Prognostic Significance ◽  
Migration And Invasion ◽  
Canonical Wnt ◽  
Acute Myeloid

Abstract Background Prickle planar cell polarity protein 1 (PRICKLE1), a core component of the non-canonical Wnt/planar cell polarity (PCP) pathway, was recently reported to be upregulated and correlated with poor prognosis in solid cancers. However, the effect of PRICKLE1 on acute myeloid leukemia (AML) remains unknown. This study aims to characterize the prognostic significance of PRICKLE1 expression in patients with AML. Methods RNA-seq was performed to compare mRNA expression profiles of AML patients and healthy controls. qRT-PCR and western blotting were used to analyze the expression of PRICKLE1 in AML patients and cell lines, and two independent datasets (TCGA-LAML and TARGET-AML) online were used to validate the expression results. The correlations between the expression of PRICKLE1 and clinical features were further analyzed. Results Our data showed that PRICKLE1 expression levels were markedly high in AML patients at the time of diagnosis, decreased after complete remission and increased again at relapse. Of note, PRICKLE1 was highly expressed in drug resistant AML cells and monocytic-AML patients. High PRICKLE1 expression was found in FLT3/DNMT3A/IDH1/IDH2-mutant AML and associated with poor prognosis. Furthermore, high expression of PRICKLE1 may be correlated with migration and invasion components upregulation in AML patients. Conclusions These results indicated that high PRICKLE1 expression may be a poor prognostic biomarker and therapeutic target of AML.

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