Transcription Factors LEF1, PU.1 and IRF8 Have Decreased Expression Levels in Majority of De Novo Acute Myeloid Leukemia Patients

2018 ◽  
Vol 16 (2) ◽  
pp. 207-217
Author(s):  
Fatemeh Salarpour ◽  
Kourosh Goudarzipour ◽  
Mohammad Hossein Mohammadi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Levels ◽  
Acute Myeloid

Overexpression of BAMBI and SMAD7 impacts prognosis of acute myeloid leukemia patients: A potential TERT non-canonical role

2021 ◽  
pp. 1-12
Author(s):  
Miral Magdy Shehata ◽  
Al-Aliaa Mohamed Sallam ◽  
Mary Gamal Naguib ◽  
Hala Osman EL-Mesallamy
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Transforming Growth Factor ◽  
De Novo ◽  
Transforming Growth Factor Β ◽  
Expression Levels ◽  
Real Time Quantitative Pcr ◽  
Kaplan Meier ◽  
De Novo Aml ◽  
Acute Myeloid

BACKGROUND: Bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) and mothers against decapentaplegic homolog 7 (SMAD7) are important transforming growth factor-β (TGF-β) signaling antagonists, however their roles in acute myeloid leukemia (AML) remains unclear. Telomerase reverse transcriptase (TERT) may be involved in regulating BAMBI and SMAD7 expressions; a role beyond telomeres that is not clinically validated yet. OBJECTIVE: In this study, we examined the expression levels and prognostic values of BAMBI, SMAD7 and TERT and their association with AML patients’ outcomes. METHODS: Blood samples were collected from 74 de-novo AML patients and 16 controls. Real-time quantitative PCR (qRT-PCR) was performed to analyze BAMBI, SMAD7 and TERT expressions. RESULTS: BAMBI and SMAD7 expression in AML were significantly upregulated versus controls (p< 0.05). BAMBI, SMAD7 and TERT levels were significantly correlated together (p< 0.001). Kaplan-Meier analysis indicated that patients with high BAMBI, SMAD7 and TERT expression levels had markedly shorter event free survival (EFS) and overall survival (OS) time (p< 0.01). Furthermore, multivariate analysis revealed that only high BAMBI expression was an independent risk factor for OS (p= 0.001). CONCLUSIONS: BAMBI is a novel biomarker in predicting prognosis in AML patients. Moreover, a potential interplay is found between BAMBI, SMAD7 and TERT in AML pathogenies.

scholarly journals The Clinical Association and Prognostic Impact of IL1RAP Expression in Patients with De Novo Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2705-2705
Author(s):  
Chao-Hung Wei ◽  
Cheng-Hong Tsai ◽  
Jih-Luh Tang ◽  
Yuan-Yeh Kuo ◽  
Feng-Ming Tien ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Underlying Mechanism ◽  
Prognostic Impact ◽  
Low Expression ◽  
Acute Myeloid

Introduction One of the contributing factors to the relapse of acute myeloid leukemia (AML) is the presence of leukemia stem cells (LSCs). Interleukin 1 receptor accessory protein (IL1RAP) was reported to be one of the LSC markers. Most studies regarding clinical implications of IL1RAP expression in AML focused on small and selected patient groups. Besides, its correlation with other molecular alterations has not been reported yet in literature. In this study, we aimed to elucidate the relationship between bone marrow IL1RAP expression level and clinical and biological features in patients with de novo non-M3 AML. Furthermore, we would like to explore its prognostic impact and potential underlying mechanism. Method We enrolled 275 newly diagnosed de novo non-M3 AML patients. Among them, 187 (68%) patients received standard induction chemotherapy and 2-4 courses of high-dose cytarabine based post-remission therapy. Analyses of 54 gene mutations were performed by next generation sequencing. The global gene expressions were profiled with the Affymetrix GeneChip Human Transcriptome Array 2.0. Result We used the median as the cut-off value to define the higher and lower IL1RAP expression groups. The patients with higher IL1RAP expression had significantly higher white blood cell counts at diagnosis, higher peripheral blast counts, and higher lactate dehydrogenase levels. Higher IL1RAP expression was closely associated with t(8;21), favorable-risk cytogenetics based on the refined MRC classification, but inversely with unfavorable-risk cytogenetics. Compared with low-expression patients, the high-expression patients had significantly more FLT3/ITD and KIT mutations, but less mutations in U2AF1, TP53, or CEBPA. Among the 187 patients receiving standard intensive chemotherapy, those with lower IL1RAP expression had significantly longer overall survival (OS) than those with higher expression (P=0.047) after a median follow-up time of 91.1 months, but disease-free survival (DFS) was not significantly different between the two groups (P=0.311). Among the 77 patients who relapsed after first complete remission (CR), the second CR rate was similar between the two groups (P=0.649), but the second DFS was significantly longer in the low-expression patients than the high-expression patients (P=0.028) which was also reflected in a significantly longer survival after first relapse in the former group than the latter group (P=0.014). The prognostic impact of IL1RAP expression on OS could be externally validated in the TCGA cohort (P=0.038). Its prognostic implication remained significant in the subgroup of our cohort with intermediate-risk cytogenetics (P=0.006) and those with normal karyotype (P=0.025). In multivariate analysis incorporating age, transplantation status, 2017 ELN risk-stratification and IL1RAP expression as covariates, the higher IL1RAP expression was an independent poor prognostic factor for OS (HR=1.555, P=0.025). The Gene Set Enrichment Analysis revealed significant up-regulation of LSC related genes in the higher IL1RAP expressed patients (Figure 1 and 2). We further profiled genome-wide RNA expression with 70,523 probes to survey the potential molecular mechanisms underlying the IL1RAP expression signature. Totally, 313 differentially expressed genes were identified (>1.5-fold change and Student t-test P<0.0001, Figure 3). We used Ingenuity Pathway Analysis (Qiagen) to analyze the possible underlying mechanism and found that the top upstream regulators were transcription factors, such as GATA1/GATA2 (P=1.39*10-11 and 1.61*10-10, respectively), and ABCB6 (P=3.84*10-8), one of the ATP-Binding Cassette transporter superfamily. The hub genes in the regulation network included ELAVL1 and NFκB, in addition to GATA1 and GATA2. Conclusion Higher IL1RAP expression is associated with distinct clinical and genetic alterations. It is an independent prognostic factor for OS irrespective of the risk category based on the ELN classification. Transcription factors, such as GATA1 and GATA2, ABCB6, ELAVL1 and NFκB might be involved in the underlying mechanism. Further prospective large cohort is warrant to validate our findings. Disclosures Tien: Novartis: Other: Travel Grant. Hou:Celgene: Research Funding; Abbvie, Astellas, BMS, Celgene, Chugai, Daiichi Sankyo, IQVIA, Johnson & Johnson, Kirin, Merck Sharp & Dohme, Novartis, Pfizer, PharmaEssential, Roche, Takeda: Honoraria. Tien:Daiichi Sankyo: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Alexion: Honoraria; Celgene: Honoraria; Johnson &Johnson: Honoraria; Novartis: Honoraria; Celgene: Research Funding; BMS: Honoraria; Pfizer: Honoraria; Roche: Research Funding.

High Expression Levels of Iaps Predict Poor Overall Survival in Childhood De Novo Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4396-4396
Author(s):  
Ingo Tamm ◽  
Stephan Richter ◽  
Doreen Oltersdorf ◽  
Ursula Creutzig ◽  
Jochen Harbott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
High Expression ◽  
Prognostic Impact ◽  
Poor Overall Survival ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Apoptosis-related proteins are important molecules for predicting chemotherapy response and prognosis in adult acute myeloid leukemia (AML). However, data on the expression and prognostic impact of these molecules in childhood AML are rare. Using flow cytometry and western blot analysis, we therefore investigated 45 leukemic cell samples of children with de novo AML enrolled and treated within the German AML-BFM93 study for the expression of apoptosis-regulating proteins (CD95, Bcl-2, Bax, Bcl-xL, Procaspase-3, XIAP, cIAP-1, Survivin). XIAP (p&lt;0.002) but no other apoptosis regulators showed maturation-dependent expression differences as determined by FAB morphology with the highest expression levels observed within the immature M0/1 subtypes. XIAP (p&lt;0.01) and Bcl-xL (p&lt;0.01) expression was lower in patients with favorable than intermediate/poor cytogenetics. After a mean follow-up of 34 months, a shorter overall survival was associated with high expression levels of XIAP {30 (n=10) vs. 41 months (n=34); p&lt;0.05} and Survivin {27 (n=10) vs. 41 months (n=34); p&lt;0.05}. We conclude that apoptosis-related molecules are associated with maturation stage, cytogenetic risk groups and therapy outcome in childhood de novo AML. The observed association of XIAP with immature FAB types, intermediate/poor cytogenetics and poor overall survival should be confirmed within prospective pediatric AML trials.

scholarly journals BAALC and ERG expression levels are associated with outcome and distinct gene and microRNA expression profiles in older patients with de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study

Blood ◽  
2010 ◽  
Vol 116 (25) ◽  
pp. 5660-5669 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Kati Maharry ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Expression Profiles ◽  
Microrna Expression ◽  
Prognostic Impact ◽  
Expression Levels ◽  
Distinct Gene ◽  
Acute Myeloid

AbstractBAALC and ERG expression levels are prognostic markers in younger (< 60 years) cytogenetically normal acute myeloid leukemia (CN-AML) adults; their prognostic impact in older (≥ 60 years) patients requires further investigation. We evaluated pretreatment expression of BAALC and ERG in 158 de novo patients treated on cytarabine/daunorubicin-based protocols. The patients were also characterized for other established molecular prognosticators. Low BAALC and ERG expression levels were associated with better outcome in univariable and multivariable analyses. Expression levels of both BAALC and ERG were the only factors significantly associated with overall survival upon multivariable analysis. To gain biological insights, we derived gene expression signatures associated with BAALC and ERG expression in older CN-AML patients. Furthermore, we derived the first microRNA expression signatures associated with the expression of these 2 genes. In low BAALC expressers, genes associated with undifferentiated hematopoietic precursors and unfavorable outcome predictors were down-regulated, whereas HOX genes and HOX-gene–embedded microRNAs were up-regulated. Low ERG expressers presented with down-regulation of genes involved in the DNA-methylation machinery, and up-regulation of miR-148a, which targets DNMT3B. We conclude that in older CN-AML patients, low BAALC and ERG expression associates with better outcome and distinct gene and microRNA expression signatures that could aid in identifying new targets and novel therapeutic strategies for older patients.

scholarly journals Upregulation of HOTAIR Predicts Poor Outcome in Acute Myeloid Leukemia

2019 ◽  
pp. 1-7
Author(s):  
Nashwa EL-Khazragy ◽  
Magdy m. Mohamed ◽  
Odett M. Zaky
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Disease Outcome ◽  
Transcriptional Level ◽  
Hematopoietic Malignancy ◽  
Expression Levels ◽  
De Novo Aml ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, in spite of the marked improvement in the treatment of AML; Molecular biomarkers open the door to improve disease outcome. Accumulating evidence suggested that the long non-coding RNA “HOTAIR” has an oncogenic role in hemopoietic malignancies. Recently, it has been evident that knockdown of HOTAIR inhibits cell proliferation and induces apoptosis by modulating c-Kit expression via acting as competing for endogenous RNAs (ceRNAs) to sponge miR-193a at the post-transcriptional level. Objectives: we aimed to evaluate the diagnostic and prognostic value of HOTAIR in AML, to investigate its association with and c-Kit and miR-193a. Subjects & Methods: we examined the expression levels of HOTAIR, miR-193a, and c-Kit in 100 de-novo AML patients using quantitative, the association of genes expressions with risk factors and patient’s outcome were statistically analyzed. Results: the expression of HOTAIR was significantly upregulated by four folds in AML compared to healthy controls; higher expression levels were associated with high-risk factors, poorer overall survival (OS) and shorter leukemia-free survival (LFS). In addition; a negative correlation was detected between Lnc-HOTAIR and miR-193a, although significance didn’t reach. Conclusion: The obtained results suggested that HOTAIR expression was upregulated in peripheral blood samples of de-novo AML patients and was associated with leukemic burden and disease outcome. Therefore, it may represent an effective diagnostic and poor prognostic tool for AML.

scholarly journals Clinical Impact of KMT2C and SPRY4 Expression Levels in Intensively Treated Younger Adult Acute Myeloid Leukemia Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1663-1663
Author(s):  
Sabine Kayser ◽  
Maximilian Feszler ◽  
Julia Krzykalla ◽  
Matthias Schick ◽  
Thomas Hielscher ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
De Novo ◽  
Prognostic Impact ◽  
Risk Class ◽  
Expression Levels ◽  
Blast Cells ◽  
Pharmaceutical Industries ◽  
Acute Myeloid

Abstract Background:Recent publications suggest important roles of lysine methyltransferase 2C (KMT2C, located on 7q) and sprouty 4 (SPRY4, located on 5q) as candidate genes in leukemogenesis of acute myeloid leukemia (AML). The prognostic impact of the gene expression levels (ELs) of both genes on outcome in AML patients (pts) is currently unclear. Aim:To evaluate the prognostic impact of KMT2C and SPRY4 expression in correlation to clinical characteristics and genetic abnormalities assessed at diagnosis in a cohort of intensively treated adult AML pts. Methods: We retrospectively studied 268 AML pts (median age, 48 years; range, 17-60 years) who had been enrolled on 2 AML SHG trials (0295 and 0199, n=148; only normal cytogenetics pts (CN)) and the SAL-AML2003 trial (n=120; only abnormal cytogenetics pts (CA)). Acute promyelocytic and core-binding factor leukemia pts were excluded. Type of AML was de novo in 235 (88%), secondary in 19 (7%) and therapy-related in 14 (5%) of the 268 pts. Regarding baseline characteristics, CN pts had significantly higher white blood counts (WBC; p=0.001) and blast cells in peripheral blood (p=0.02) as compared to CA pts; all other factors were comparable. Cytogenetic analyses could be performed in 263 (98%) of the 268 pts. Cytogenetic risk classification according to ELN guidelines was intermediate-II in 55 (47%) and adverse in 63 (53%) of the CA pts, respectively. Abnormalities (abn) of 5q were present in 21 (18%) and abn of 7q in 16 (14%) of the CA pts. NPM1 and FLT3-ITD were analyzed in 145 (98%) of the CN pts. Of those, 59 (41%) were only NPM1 positive (pos), 12 (8%) were only FLT3-ITD pos, 34 (23%) were double pos and 40 (28%) were double negative (neg). KMT2C and SPRY4 ELs, normalized to ABL1and log2-transformed for analysis, were measured in triplets on cDNA obtained at diagnosis by RT-qPCR. Based on cDNA availability, KMT2C ELs could be analyzed in 143 (97%) of the CN and in all of the 120 CA pts, respectively. SPRY4 ELs could be measured in 30 (21%) of the CN and 107 (89%) of the CA pts, respectively. Results: KMT2C ELs were significantly lower in CN pts with de novo as compared to secondary AML (p= 0.02), whereas there was no difference in CA pts. No significant association was found for SPRY4 and type of AML. KMT2C ELs were significantly lower in FLT3-ITD pos as compared to FLT3-ITD neg CN pts (p=0.046), whereas there was no difference for SPRY4 ELs between the two groups (p=0.57). In addition, there was a significantly lower KMT2C expression in CN pts with intermediate-I risk as compared to NPM1 pos / FLT3-ITD neg pts (p=0.01). Regarding CA pts, there was no difference of KMT2C or SPRY4 ELs in adverse as compared to intermediate-II risk pts (p=0.08; p=0.20, respectively). When focusing on specific subgroups, KMT2C ELs were significantly lower in abn7q CA pts as compared to those without abn7q (p=0.002), whereas there was no difference of SPRY4 ELs in CA pts with or without abn5q (p=0.27). In univariate analysis higher SPRY4 ELs showed a significant favorable impact on relapse-free (RFS, p=0.03) and a trend towards a beneficial impact on overall survival (OS, p=0.06) for CA patients. A similar effect for KMT2C was not observed (RFS, p=0.96; OS, p=0.92). In subgroup analyses of pts with adverse risk cytogenetics, there was no impact of KMT2C or SPRY4 ELs on RFS (p=0.73; p=0.39) or OS (p=0.49; p=0.46), respectively. The same was true for FLT3-ITD pos CN pts (RFS, p=0.73; p=0.37; OS, p=0.91; p=0.36, respectively). In multivariate analyses on RFS and OS in CA pts including age, gender, KMT2C and SPRY4 ELs, logarithm of WBC, blast cells in bone marrow and cytogenetic risk group as variables, only higher age (OS, Hazard ratio (HR),1.28 per 10 years; 95%-confidence interval (CI): 1.02-1.59; p=0.03) and complex karyotype as compared to intermediate-II risk cytogenetics (RFS, HR: 2.25; 95%-CI: 1.20-4.22; p=0.01; OS, HR: 2.97; 95%-CI: 1.65-5.35; p<0.001) had an adverse impact. An effect of KMT2C or SPRY4 on RFS (p=0.84; p=0.16) or OS (p=0.85; p=0.45) was not found in the multivariate setting. In addition, in a multivariate model on CN pts (risk class according to NPM1 and FLT3-ITD mutational status instead of cytogenetic risk class) neither KMT2C nor SPRY4 had an impact on RFS (p=0.13; p=0.39, respectively) or OS (p=0.36; p=0.56, respectively). Conclusions:Lower KMT2C and SPRY4 ELs are associated with distinct genetic risk groups. An impact on prognosis was evident in univariable analyses for SPRY4 but not for KMT2C ELs in CA pts. Disclosures Kayser: Novartis: Consultancy. Platzbecker:Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Heuser:Tetralogic: Research Funding; Novartis: Consultancy, Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Thiede:AgenDix: Employment, Other: Ownership.

AML1/RUNX1 mutations in 470 adult patients with de novo acute myeloid leukemia: prognostic implication and interaction with other gene alterations

Blood ◽  
2009 ◽  
Vol 114 (26) ◽  
pp. 5352-5361 ◽  
Author(s):  
Jih-Luh Tang ◽  
Hsin-An Hou ◽  
Chien-Yuan Chen ◽  
Chieh-Yu Liu ◽  
Wen-Chien Chou ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Rate ◽  
Adult Patients ◽  
Poor Prognostic Factor ◽  
The Impact ◽  
Runx1 Mutation ◽  
Acute Myeloid

AbstractSomatic mutation of the AML1/RUNX1(RUNX1) gene is seen in acute myeloid leukemia (AML) M0 subtype and in AML transformed from myelodysplastic syndrome, but the impact of this gene mutation on survival in AML patients remains unclear. In this study, we sought to determine the clinical implications of RUNX1 mutations in 470 adult patients with de novo non-M3 AML. Sixty-three distinct RUNX1 mutations were identified in 62 persons (13.2%); 32 were in N-terminal and 31, C-terminal. The RUNX1 mutation was closely associated with male sex, older age, lower lactic dehydrogenase value, French-American-British M0/M1 subtypes, and expression of HLA-DR and CD34, but inversely correlated with CD33, CD15, CD19, and CD56 expression. Furthermore, the mutation was positively associated with MLL/PTD but negatively associated with CEBPA and NPM1 mutations. AML patients with RUNX1 mutations had a significantly lower complete remission rate and shorter disease-free and overall survival than those without the mutation. Multivariate analysis demonstrated that RUNX1 mutation was an independent poor prognostic factor for overall survival. Sequential analysis in 133 patients revealed that none acquired novel RUNX1 mutations during clinical courses. Our findings provide evidence that RUNX1 mutations are associated with distinct biologic and clinical characteristics and poor prognosis in patients with de novo AML.

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