scholarly journals Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 436 ◽  
Author(s):  
Victor Pallarès ◽  
Montserrat Hoyos ◽  
M. Chillón ◽  
Eva Barragán ◽  
M. Prieto Conde ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Prognostic Markers ◽  
Response To Treatment ◽  
Intermediate Risk ◽  
Patient Subgroup ◽  
Acute Myeloid

In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment.

Molecular Markers Predicting Clinical Outcome in Patients with Intermediate-Risk Acute Myeloid Leukemia Receiving Autologous Stem Cell Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 604-604
Author(s):  
Jordi Esteve ◽  
Susana Kalko ◽  
Montserrat Torrebadell ◽  
Mireia Camos ◽  
Pedro Jares ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Intermediate Risk ◽  
Npm1 Mutation ◽  
Acute Myeloid

Abstract Post-remission therapy in patients with acute myeloid leukemia (AML) is assigned according to the predictable biological risk of the disease, mainly based on cytogenetics. Nonetheless, optimal post-remission strategy for the intermediate-risk subtype, given the prognostic heterogeneity of this category, is currently undefined. Analysis of potentially relevant molecular features within this subgroup might contribute to clarify the role of autologous stem cell transplantation (autoHSCT) in these patients. Thirty seven patients (age: 53, 15–66; 51% female) diagnosed with intermediate-risk de novo AML during the period 1994–2006 who received an autoHSCT in first complete response were included in the study. Pre-transplant therapy was similar in all patients, consisting of standard induction chemotherapy (ICE, n=8, IDICE, n=29) and one cycle of high-dose ara-C-based consolidation chemotherapy. Internal tandem duplication of flt-3 (flt-3 ITD) and exon 12 NPM1 mutations were studied by either PCR or RT-PCR following standard methods. Gene expression profiling was examined in 28 patients with oligonucleotide HGU133 Plus 2.0 arrays (Affymetrix). Gene expression measures were normalized using RMA methodology (Affy package), and dChip v1.3 and Limma software (Bioconductor) were used for unsupervised and supervised analyses. In order to identify genes with prognostic value, a supervised analysis based on patients’ outcome (relapsed patients vs. long-term responders, i.e. >2-year duration) was performed. The combined results of NPM mutation and flt-3 ITD defined three subgroups of patients with different outcome: group 1 (n=12), constituted by patients with mutated NPM1 without flt-3 ITD; group 2 (n=20), which included patients with neither NPM1 mutation or flt-3 ITD; and group 3 (n=5), defined by flt-3 ITD regardless NPM1 mutational status. Thus, 5-year survival of these 3 subgroups of patients was 91%±9%, 52%±12%, and 20%±18%, respectively (p=0.02; see figure). Preliminary results of multiple gene profile comparisons between subgroups of patients with different outcome disclosed a cluster of genes with differential expression. Thus, in the most significant balanced comparison, 1238 genes were found to vary significantly in the unsupervised analysis, and 109 differentially expressed genes were identified in the supervised analysis. Interestingly, overexpression of genes such as TNF, RETN, CFLAR, SLC16A7, ENG, CD48, PLCR1, and SULTB1 correlated with a high relapse risk, whereas increased expression of YY1, FBXL12 and EXOSC6 were associated with a favorable outcome. In conclusion, presence of NPM1 mutation and flt-3 ITD are strong predictors of the outcome after autoHSCT in patients with intermediate-risk AML. Furthermore, genome-wide analysis may contribute to further define gene clusters with prognostic significance in patients with cytogenetically intermediate-risk AML receiving autoHSCT as consolidation therapy. Figure Figure

Presence of FLT3-ITD and high BAALC expression are independent prognostic markers in childhood acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (22) ◽  
pp. 5905-5913 ◽  
Author(s):  
Anna Staffas ◽  
Meena Kanduri ◽  
Randi Hovland ◽  
Richard Rosenquist ◽  
Hans Beier Ommen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Npm1 Mutation ◽  
Mutation Status ◽  
Expression Levels ◽  
Pediatric Aml ◽  
Gene Expression Levels ◽  
Acute Myeloid

Abstract Mutation status of FLT3, NPM1, CEBPA, and WT1 genes and gene expression levels of ERG, MN1, BAALC, FLT3, and WT1 have been identified as possible prognostic markers in acute myeloid leukemia (AML). We have performed a thorough prognostic evaluation of these genetic markers in patients with pediatric AML enrolled in the Nordic Society of Pediatric Hematology and Oncology (NOPHO) 1993 or NOPHO 2004 protocols. Mutation status and expression levels were analyzed in 185 and 149 patients, respectively. Presence of FLT3-internal tandem duplication (ITD) was associated with significantly inferior event-free survival (EFS), whereas presence of an NPM1 mutation in the absence of FLT3-ITD correlated with significantly improved EFS. Furthermore, high levels of ERG and BAALC transcripts were associated with inferior EFS. No significant correlation with survival was seen for mutations in CEBPA and WT1 or with gene expression levels of MN1, FLT3, and WT1. In multivariate analysis, the presence of FLT3-ITD and high BAALC expression were identified as independent prognostic markers of inferior EFS. We conclude that analysis of the mutational status of FLT3 and NPM1 at diagnosis is important for prognostic stratification of patients with pediatric AML and that determination of the BAALC gene expression level can add valuable information.

Evaluation of CDCP1 (CD318) and endoglin (CD105) expression as prognostic markers in acute myeloid leukemia

2021 ◽  
pp. 1-12
Author(s):  
Huda F. Ebian ◽  
Dina R. Issa ◽  
Amira S. Al-Karamany ◽  
Rasha L. Etewa ◽  
Hanaa M. El Maghraby ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Markers ◽  
Poor Response ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
Cub Domain ◽  
Poor Outcomes ◽  
Wbc Count ◽  
Acute Myeloid

BACKGROUND: The most commonly used prognostic factors in acute myeloid leukemia (AML) are cytogenetic, molecular, and morphological markers. However, AML prognosis is still unfavorable particularly in adults. So, further reliable markers are urgently needed to improve the risk stratification and treatment decisions. CUB domain-containing protein 1 (CDCP1; CD318) and endoglin (CD105) are new markers correlated with poor prognosis in different solid tumors, but their role in AML prognosis is not fully evaluated. OBJECTIVES: This work aimed to evaluate the prognostic role of CD318 and CD105 in AML and their impact on the outcomes. METHODS: Sixty-five newly diagnosed AML patients were included in this study. CD318 and CD105 expression was assessed by quantitative real-time polymerase chain reaction. Patients were followed up for ∼ 2 years to evaluate the prognostic impact of gene expression on the outcomes. RESULTS: Patients with high CD318 and CD105 showed higher white blood cell (WBC) count, M2 subtype, poor cytogenetic risk, reduced complete remission, and a greater number of deaths compared to low CD318 and CD105. CD318 was correlated with CD105, and both were correlated with WBC count, bone marrow blasts, and peripheral blood blasts. After a follow-up period of up to 24 months, relapse-free survival for high CD318 and CD105 was significantly different (42.1% and 52.6% vs. 64.5% and 58.1% for low CD318 and CD105, respectively). Survival was worse in patients with high CD318 and CD105, as the mean survival time was 13.9 and 13.3 months compared to 24 and 22.7 months in low CD318 and CD105, respectively. CONCLUSIONS: CD318 and CD105 are upregulated in AML patients. Their overexpression was associated with poor response to treatment and poor outcomes. Therefore, CD318 and CD105 can be useful prognostic markers in 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.

Acute Myeloid Leukemia With Isolated Trisomy 13 Is a Genetically Homogenous Entity With a High Frequency Of Mutations In Genes Encoding Components Of The Splicing Machinery and Extremely Poor Prognosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 608-608 ◽  
Author(s):  
Tobias Herold ◽  
Klaus H. Metzeler ◽  
Sebastian Vosberg ◽  
Stephanie Schneider ◽  
Max Hubmann ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Exome Sequencing ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Clinical Course ◽  
Gene Set Enrichment Analysis ◽  
Trisomy 13 ◽  
Acute Myeloid ◽  
Splicing Machinery

Abstract Acute myeloid leukemia (AML) with isolated trisomy 13 (AML+13) is rare and frequently associated with FAB M0 morphology. The clinical course is not well characterized but according to the ELN classification of intermediate prognosis. Eighty to one-hundred percent of patients (pts) with AML+13 carry mutations in the RUNX1 gene. Over-expression of FLT3 (located on chromosome 13 [chr 13]) due to the additional gene copy on the third chr 13 was proposed as a mechanism of leukemogenesis in AML+13 (gene dosage hypothesis). We set out to characterize the clinical course of AML+13 pts and elucidate their molecular background using whole exome sequencing, targeted resequencing and gene expression profiling. We identified 23 pts with AML+13 enrolled in a multicenter trial of the German AML Cooperative Group (AMLCG-1999) and compared this group to 386 pts without +13 who were classified in the ELN Intermediate-II genetic category. All pts received intensive induction chemotherapy. There was no significant difference in age, white blood cell or platelet count between the two groups. However, LDH levels were significantly (p=.01) lower in the AML+13 group while bone marrow blast percentage was significantly higher (p=.04). Twelve AML+13 pts (52%) reached complete remission, but all relapsed. Relapse-free and overall survival were inferior in the AML+13 group compared to other ELN Intermediate-II pts (median RFS, 9 vs 15 months, p=.01; median OS, 7 vs. 13 months, p=.03). Remission samples from two AML+13 pts were available as normal control for exome sequencing. Using SureSelect human all exon target enrichment (Agilent) followed by 80bp paired-end sequencing on an Illumina GAIIx platform, we were able to identify non-synonymous leukemia-specific mutations affecting, among others, RUNX1, ASXL1, PTPN11 and CEBPZ. Genes identified by exome sequencing and a panel of genes recurringly mutated in AML were studied by targeted amplicon resequencing in all AML+13 pts with available material (16/23; Figure). As described before, a high incidence of RUNX1 mutations (75%) was identified. In addition, we detected mutations in spliceosome components in 14/16 (88%) of AML+13 pts, including SRSF2 codon 95 mutations in 13/16 pts (81%). One patient without SRSF2 mutation showed a mutation in SF3B1. Moreover, recurring mutations were found in ASXL1 (44%) and BCOR (25%), and were associated with RUNX1 and SRSF2 mutations. Interestingly, both pts without mutations in the splicing machinery had mutations in DNMT3A, which were also mutually exclusive with mutations in RUNX1 or ASXL1. Two pts carried mutations in CEBPZ suggesting that CEBPZ is a novel recurringly mutated gene in AML.FigureMutation frequencies in 16 patients with AML+13Figure. Mutation frequencies in 16 patients with AML+13 To further characterize this genetically homogenous subgroup, we compared gene expression profiles of 9 pts with AML+13 with 509 AML pts without +13. We identified 678 (up-regulated 492; down-regulated 186) probe sets as significantly deregulated. Only 59 (8.7%) of these probe sets were localized on chr 13, but of those, 55 were up-regulated and only 4 were down-regulated. Up-regulated probe sets on chr 13 included FOXO1, FLT3 and RB1. The strongest down-regulated probe set on chr 13 belonged to the tumor suppressor gene SPRY2, which is a negative regulator of receptor tyrosine kinases. Gene set enrichment analysis showed significant deregulation of gene sets associated with regulation of transcription and nuclear transport. In summary, our study is the first to show that AML+13 is significantly associated with inferior OS and RFS compared to other intermediate-risk cytogenetic abnormalities in a homogeneously treated cohort. Furthermore, we present evidence that AML+13 leukemias are a genetically quite homogenous subgroup. AML+13 is not only associated with a high rate of RUNX1 mutations but also with mutations in SRFS2, ASXL1 and BCOR. The incidence of mutations in SRSF2 in AML+13 is the highest of any AML subgroup reported so far. In addition, our gene expression data show a homogenous expression profile associated with AML+13. The striking association of a few recurring mutations in AML+13 suggests a biological relationship with synergistic lesions during leukemogenesis. While mutations in RUNX1, ASXL1 and up-regulation of FLT3 were previously reported as markers of poor prognosis in AML, the combination of these lesions might be responsible for the extremely poor outcome of AML+13. Disclosures: Krebs: Illumina: Honoraria. Greif:Illumina: Honoraria.

scholarly journals Elevated SPINK2 gene expression is a predictor of poor prognosis in acute myeloid leukemia

2019 ◽  
Author(s):  
Cuiling Xue ◽  
Jialing Zhang ◽  
Guiju Zhang ◽  
Yuyan Xue ◽  
Guiyan Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Acute Myeloid
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