Low SOX17 expression: prognostic significance in de novo acute myeloid leukemia with normal cytogenetics

2014 ◽  
Vol 52 (12) ◽  
Author(s):  
Chun-yan Tang ◽  
Jiang Lin ◽  
Wei Qian ◽  
Jing Yang ◽  
Ji-chun Ma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Quantitative Pcr ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Aberrant Expression ◽  
Real Time Quantitative Pcr ◽  
The Status ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract: Aberrant expression of SRY-box containing gene 17 (: Real-time quantitative PCR (RQ-PCR) was performed to analyze the status of:Our findings indicated that low

scholarly journals Distinct clinical and biological characteristics of acute myeloid leukemia with higher expression of long noncoding RNA KIAA0125

2020 ◽  
Author(s):  
Yu-Hung Wang ◽  
Chien-Chin Lin ◽  
Chia-Lang Hsu ◽  
Sheng-Yu Hung ◽  
Chi-Yuan Yao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Noncoding Rna ◽  
De Novo ◽  
Remission Rate ◽  
Prognostic Significance ◽  
Multivariable Analysis ◽  
Disease Free Survival ◽  
Biological Characteristics ◽  
Acute Myeloid

AbstractExpression of long non-coding RNA KIAA0125 has been incorporated in various gene expression signatures for prognostic prediction in acute myeloid leukemia (AML) patients, yet its functions and clinical significance remain unclear. This study aimed to investigate the clinical and biological characteristics of AML bearing different levels of KIAA0125. We profiled KIAA0125 expression levels in bone marrow cells from 347 de novo AML patients and found higher KIAA0125 expression was closely associated with RUNX1 mutation, but inversely correlated with t(8;21) and t(15;17) karyotypes. Among the 227 patients who received standard chemotherapy, those with higher KIAA0125 expression had a lower complete remission rate, shorter overall survival (OS) and disease-free survival (DFS) than those with lower expression. The prognostic significance was validated in both TCGA and GSE12417 cohorts. Subgroup analyses showed that higher KIAA0125 expression also predicted shorter DFS and OS in patients with normal karyotype or non-M3 AML. In multivariable analysis, higher KIAA0125 expression remained an adverse risk factor independent of age, WBC counts, karyotypes, and mutation patterns. Bioinformatics analyses revealed that higher KIAA0125 expression was associated with hematopoietic and leukemic stem cell signatures and ATP-binding cassette transporters, two predisposing factors for chemoresistance.

scholarly journals Low expression of MN1 associates with better treatment response in older patients with de novo cytogenetically normal acute myeloid leukemia

Blood ◽  
2011 ◽  
Vol 118 (15) ◽  
pp. 4188-4198 ◽  
Author(s):  
Sebastian Schwind ◽  
Guido Marcucci ◽  
Jessica Kohlschmidt ◽  
Michael D. Radmacher ◽  
Krzysztof Mrózek ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Hox Genes ◽  
De Novo ◽  
Prognostic Significance ◽  
The Impact ◽  
Favorable Group ◽  
Acute Myeloid

AbstractLow MN1 expression bestows favorable prognosis in younger adults with cytogenetically normal acute myeloid leukemia (CN-AML), but its prognostic significance in older patients is unknown. We analyzed pretherapy MN1 expression in 140 older (≥ 60 years) de novo CN-AML patients treated on cytarabine/daunorubicin-based protocols. Low MN1 expressers had higher complete remission (CR) rates (P = .001), and longer overall survival (P = .03) and event-free survival (EFS; P = .004). In multivariable models, low MN1 expression was associated with better CR rates and EFS. The impact of MN1 expression on overall survival and EFS was predominantly in patients 70 years of age or older, with low MN1 expressers with mutated NPM1 having the best outcome. The impact of MN1 expression was also observed in the Intermediate-I, but not the Favorable group of the European LeukemiaNet classification, where low MN1 expressers had CR rates and EFS similar to those of Favorable group patients. MN1 expresser-status-associated gene- and microRNA-expression signatures revealed underexpression of drug resistance and adverse outcome predictors, and overexpression of HOX genes and HOX-gene–embedded microRNAs in low MN1 expressers. We conclude that low MN1 expression confers better prognosis in older CN-AML patients and may refine the European LeukemiaNet classification. Biologic features associated with MN1 expression may help identify new treatment targets.

Expression of c-mpl mRNA, the receptor for thrombopoietin, in acute myeloid leukemia blasts identifies a group of patients with poor response to intensive chemotherapy.

1997 ◽  
Vol 15 (6) ◽  
pp. 2262-2268 ◽  
Author(s):  
M Wetzler ◽  
M R Baer ◽  
S H Bernstein ◽  
L Blumenson ◽  
C Stewart ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factor ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Poor Response ◽  
Significant Difference ◽  
De Novo Aml ◽  
Cd34 Expression ◽  
Acute Myeloid

PURPOSE c-mpl, the human homolog of v-mpl, is the receptor for thrombopoietin. Given that c-mpl expression carries an adverse prognosis in myelodysplastic syndrome and given the prognostic significance of expression of other growth factor receptors in other diseases, we attempted to determine whether c-mp/mRNA expression is a prognostic factor in acute myeloid leukemia (AML). PATIENTS AND METHODS We analyzed bone marrow samples from 45 newly diagnosed AML patients by reverse-transcription polymerase chain reaction. RESULTS Samples from 27 patients (60%) expressed c-mpl mRNA (c-mpl+); their clinical and laboratory features were compared with those of the 18 patients without detectable levels of c-mpl(c-mpl-). No significant differences in age, sex, leukocyte count, French-American-British subtype, or karyotype group were found. c-mpl+ patients more commonly had secondary AML (41% v 11%; P = .046) and more commonly expressed CD34 (67% v 12%; P = .0004). There was no significant difference in complete remission (CR) rate. However, c-mpl+ patients had shorter CR durations (P = .008; median, 6.0 v > 17.0 months). This was true when only de novo AML patients were considered and when controlling for age, cytogenetics, or CD34 expression. There was a trend toward shorter survival in c-mpl+ patients (P = .058; median, 7.8 v 9.0 months). CONCLUSION These data suggest that c-mpl expression is an adverse prognostic factor for treatment outcome in adult AML that must be considered in the analysis of clinical studies using thrombopoietin in AML.

scholarly journals Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2464-2469 ◽  
Author(s):  
AF List ◽  
CS Spier ◽  
TM Grogan ◽  
C Johnson ◽  
DJ Roe ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Secondary Aml ◽  
Lung Resistance Protein ◽  
Transporter Protein ◽  
Lung Resistance ◽  
Resistance Protein ◽  
Acute Myeloid

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein- negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.

Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA)

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 2717-2723 ◽  
Author(s):  
Claude Preudhomme ◽  
Christophe Sagot ◽  
Nicolas Boissel ◽  
Jean-Michel Cayuela ◽  
Isabelle Tigaud ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Prognosis Factor ◽  
Cebpa Mutations ◽  
Factor C ◽  
French Association ◽  
Acute Myeloid

The transcription factor C/EBPα is crucial for differentiation of mature granulocytes. Recently, differentCEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPα protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P = .02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P = .54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P = .04).FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.

Prognostic Significance of NQO1 Polymorphism and GST-M1 Deletion in De Novo Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4846-4846
Author(s):  
Yeo-Kyeoung Kim ◽  
Hee-Je Kim ◽  
Woo-Sung Min ◽  
Jong- Ho Won ◽  
Deog-Yeon Jo ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Outcomes ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Remission Induction ◽  
Repair System ◽  
Significant Difference ◽  
Normal Cytogenetics ◽  
Acute Myeloid

Abstract Background: Although the most powerful prognostic factor of acute myeloid leukemia (AML) patients is the karyotype of the leukemic blast, data have not been obtained almost entirely in patients with heterogeneous cytogenetics. Further, some patients with favorable cytogenetics may show the poor treatment outcomes. Previous reports suggested that the single nucleotide polymorphisms of genes coding drug detoxification enzymes such as cytochrome P450 family or DNA repair system may influence the treatment outcomes in the patients with AML. We evaluated the role of polymorphisms in XRCC1, XRCC4, CYP1A1, GST-T1, GST-M1, NOQ1, and NAT2*6A in predicting therapeutic outcomes of adults with AML. Methods: XRCC1 (rs25487), XRCC4 (rs1056503), NQO1 (rs1800566), CYP-4501A1*2B (rs1048943), NAT2*6A (rs1799930) gene polymorphisms and deletion of GST-M1/GST-T1 were evaluated in 460 bone marrow (BM) samples obtained at initial diagnosis from de novo AML patients. Genotyping method is pyrosequencing using genomic DNA from BM samples. Homozygous deletions of GST-M1 and GST-T1 genes were detected with a multiplex PCR technique. All patients except APL (acute promyelocytic leukemia) received one or two rounds of intensive induction chemotherapy consisting of 3 days of idarubicin and 7 days of cytarabine. APL patients treated with AIDA regimen consisting of 45 days of ATRA (all-trans retinoic acid) and 3 days of idarubicin. Results: Of total 460 patients, ninety-nine patients (21.5%) were APL. Seventy-one (15.4%) were AML with t(8;21), twenty-three (5%) were AML with inv(16), and 179 patients (38.9%) showed normal cytogenetics. The median age of patients was 44 years (range, 14–75 years). In all cytogenetic risk group, the patients carrying homozygous NQO1 gene polymorphism (TT) showed significantly lower rate of complete remission (CR) than in those with negative or heterogyzous polymorphisms (TT: 72.7% vs. CC/CT: 85.9%, p=0.03). There was no significant difference in relapse rate, leukemia-free survival (LFS) and overall survival between homo- and heterozygote groups in these polymorphsims. In subgroup analysis, APL patients carrying TT genotype in NQO1 also showed lower rate of CR (TT: 77.8% vs. CC/CT: 95.4%, p=0.04). In AML patients except APL, NQO1 homozygous polymorphsim (TT) was also associated with lower CR rate (TT: 69.6% vs. CC/CT: 84.2%, p=0.005). In normal cytogenetics, the patients with del GST-M1 showed shorter LFS compared with those carrying GST-M1 (18.0 ± 5.7ms. vs. 34.6 ± NA. p=0.04). Conclusions: This study revealed an association between NQO1 polymorphism and GST-M1 deletion and the treatment outcomes for AML patients. Further study and larger sample size are needed to reach the definite conclusion on these associations. However, a stratified treatment plan in remission induction chemotherapy such as augmentation or addition of other chemotherapeutic agents may be warranted for AML patients harvoring homozygous NQO1 polymorphism (TT) or del GST-M1.

MiR-132 and MiR-212 as Regulators of WT1 and GATA2 in Acute Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1283-1283 ◽  
Author(s):  
Maaike Luesink ◽  
Jeannet Nigten ◽  
Ruth H.J.N. Knops ◽  
Theo J.M. de Witte ◽  
Bert A. van der Reijden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Transcription Factors ◽  
Quantitative Pcr ◽  
Blood Cells ◽  
Myeloid Leukemia ◽  
Granulocytic Differentiation ◽  
Aberrant Expression ◽  
Differentiation Induction ◽  
Acute Myeloid

Abstract Abstract 1283 Poster Board I-305 Wilms' tumor 1 (WT1) and GATA binding protein 2 (GATA2) transcription factors are highly expressed in hematopoietic stem cells and progenitors. Differentiation of precursor blood cells towards mature blood cells is accompanied by rapid downregulation of both transcription factors. Overexpression of WT1 has been observed in the majority of acute myeloid leukemia (AML) cases. Furthermore, in 10-15% of the AML cases mutations in the WT1 gene occur, which have been correlated with poor prognosis. Aberrant expression of GATA2 in AML has been described as well, but no mutations in this gene have been reported in AML so far. How the (aberrant) expression of WT1 and GATA2 is controlled is not completely clear. A regulatory role for microRNAs (miRNAs) has been described for several transcription factors which regulate hematopoiesis. MiRNAs negatively regulate gene expression by translational repression or degradation of target messenger RNAs (mRNAs). In the present study we investigated the interplay between miRNAs and transcription factors that are involved in myeloid development and malignant transformation towards AML. We studied the expression of 158 miRNAs in the APL cell line NB4 during induction of granulocytic differentiation with all-trans retinoic acid (ATRA). Quantitative PCR specific for mature miRNAs was performed (Applied Biosystems). Twenty out of 158 miRNAs were more than 10-fold upregulated upon differentiation induction with ATRA. MiR-132 and miR212, which are derived from the same pri-miRNA transcript, were most strongly upregulated during ATRA-induced granulocytic differentiation (1200- and 350-fold respectively at 96 hours after ATRA-stimulation). In vitro ATRA-induction of primary APL cells also resulted in upregulation of miR-132 and miR-212. Computational target prediction algorithms were used to identify transcription factors which may be targeted by miR-132 and miR-212. Subsequently, the expression pattern of the predicted targets was determined experimentally in NB4 cells before and after differentiation induction with ATRA using microarray-based mRNA profiling (Affymetrix). In addition, further verification of target gene expression during ATRA-induced differentiation was performed using quantitative PCR. The transcription factors WT1 and GATA2 were predicted as targets of miR-132 and miR-212 by two out of four different prediction programs that were used. Both transcription factors contained putative binding sites for miR-132 and miR-212 in their 3'UTR. When tested on microarray and by quantitative PCR, the expression of WT1 and GATA2 was indeed strongly downregulated during ATRA-induced granulocytic differentiation of NB4 cells (65- and 165-fold respectively at 96 hours after ATRA stimulation) as well as in primary leukemia cells derived from APL patients (30- and 10-fold respectively at 48 hours after ATRA-stimulation). During ATRA-induced differentiation the expression levels of WT1 were positively correlated with the expression levels of GATA2. In addition, WT1 expression was also strongly correlated with GATA2 expression in a cohort of 27 pre-treatment AML cases as well as in 7 healthy controls, suggesting that these genes might be co-regulated to a large extent. To directly prove that WT1 and GATA2 are indeed targeted by miR-132 and miR-212, we are currently performing lentiviral-based overexpression studies of both miRNAs to determine the effect on endogenous WT1 and GATA2 mRNA expression. MicroRNAs which target WT1 and GATA2 may be valuable tools in controlling the aberrant expression of WT1 and GATA2 observed in AML. Disclosures No relevant conflicts of interest to declare.

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