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.

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.

scholarly journals Survival and Prognostic Factors in Adults Acute Myeloid Leukemia: A Retrospective Analysis of 119 Cases

2013 ◽  
Vol 1 (2) ◽  
pp. 70-73
Author(s):  
Alina M Gridjac ◽  
Cristian Daniel Pirlog ◽  
Anca Simona Bojan
Keyword(s):  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Risk Groups ◽  
Developed Countries ◽  
Risk Level ◽  
Secondary Aml ◽  
Cytogenetic Testing ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a malignant disease with significant identified prognostic factors. Therefore our aim was to develop an Assessment Scheme of Prognosis in AML based on prognostic factors. In some counties, such as Romania or other less-highly developed countries, this scheme would be beneficial particularly when cytogenetic testing is unavailable or time-intensive. Methods: We analyzed 119 adult patients with AML during a five year-period from a single-center in Romania. We retrospectively collected and analyzed data with Epi Info and Excel using patient medical records. Results: According to age, the group A1 (<60 years) had a 40 months survival, in contrast with the group B1 (≥60 years) with a survival of 19 months (p=0,0063). The group A2 (secondary AML) survived 15 months, whereas the group B2 (AML de novo) survived 40 months (p=0.0021). Additionally, the group A3 (mild comorbidities) achieved a 40 months survival, the group B3 (moderate comorbidities) survived 19 months, whereas the group C3 (severe comorbidities) survived 7 months (p=0,0059). According to WBC and blast number, the group A4 (high levels) had a 25 months survival, whereas the group B4 (low levels) survived 40 months (p=0,0057). Conclusion: The prognostic factors studied are useful to identify the risk level of AML disease for each patient at diagnosis. We developed an assessment scheme of prognosis with three risk groups according to age, secondary AML, comorbidity, WBC and blasts and cytogenetic examination.

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.

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.

Priming with Granulocyte-Colony Stimulating Factor Did Not Improve Outcome in a Randomized Study of Elderly Acute Myeloid Leukemia but Increased Induction Mortality.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1980-1980 ◽  
Author(s):  
Gesine Bug ◽  
Steffen Koschmieder ◽  
Juergen Krauter ◽  
Stefanie Wiebe ◽  
Carla Hannig ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Randomized Study ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Secondary Aml ◽  
To Receive ◽  
Stimulating Factor ◽  
Acute Myeloid

Abstract Introduction: In acute myeloid leukemia (AML), granulocyte-colony stimulating factor (G-CSF) has been used in combination with induction chemotherapy to improve complete remission rates (CR) by sensitization of leukemic cells. This randomized prospective oligocenter study was designed to assess whether two induction cycles given simultaneously with and followed by G-CSF (G-CSFpriming) was superior to G-CSF administered only after induction (G-CSFpost) with regard to CR and disease-free survival (DFS) in patients older than 60 years. Secondary objectives were comparison of this concept in de novo versus secondary AML and to examine the feasibility of autologous stem cell transplantation (ASCT) as late consolidation. Methods: Overall, 183 eligible pts (median age 67 yrs) were randomly assigned to receive G-CSF starting on the day before (n=91) or after chemotherapy (n=92) during two induction cycles consisting of idarubicin, cytarabine and etoposide (IdAV). The two treatment groups were evenly matched with respect to age, diagnosis and cytogenetic risk factors. G-CSF was given as daily s.c. injection at 5μg/kg. Pts achieving a CR were scheduled to receive early consolidation chemotherapy with fludarabine, cytarabine, idarubicin plus G-CSF (mini-FlagIda) and peripheral blood stem cell (PBSC) harvest, followed by ASCT as late consolidation. Pts lacking PBSC due to mobilization failure were optionally treated with a second cycle of mini-FlagIda as late consolidation. Results: After induction chemotherapy, 118 out of 183 pts (64%) achieved CR. Response was not different in the G-CSFpost vs. G-CSFpriming group (70% vs. 59%, p=0.148). Recovery of neutrophils was similar in both groups after cycle 1 (21.8 vs. 20.5 days) and cycle 2 (14.9 vs. 16.3 days). Notably, G-CSF priming resulted in a significantly increased mortality in induction 1 (25% vs. 9%, p=0.003) associated with a higher rate of severe mucositis and infectious complications. The probability of OS and DFS at 5 years was 16% and 20%, resp., with no significant differences between the induction groups. With a median follow up of 26 months (range, 5–77), 77 out of 118 complete responders have relapsed and 7 died while in CR. Patients with de novo AML had a significantly better OS than those with secondary AML (17 vs. 11 months, p<0.001). Unfavorable cytogenetics were associated with a poor median OS (7 vs. 15 months, p<0.001). Following mini-FlagIda I, collection of at least 2x10E6 CD34+ PBSC/kg was feasible in 35 of 67 pts in whom mobilization of CD34+ cells was monitored. Late consolidation with ASCT (n=19) was not superior to mini-FlagIda II (n=16, DFS 24 vs. 27 months). Conclusions: In this randomized study with elderly AML patients, G-CSF priming did not result in an increased CR rate and was associated with higher induction mortality, but OS was not influenced. We demonstrated feasibility of ASCT in patients up to the age of 70 years, which was not superior to chemotherapy consolidation.

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