scholarly journals Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3578-3584 ◽  
Author(s):  
Felicitas Thol ◽  
Sofia Kade ◽  
Carola Schlarmann ◽  
Patrick Löffeld ◽  
Michael Morgan ◽  
...  

Abstract Mutations in genes of the splicing machinery have been described recently in myelodysplastic syndromes (MDS). In the present study, we examined a cohort of 193 MDS patients for mutations in SRSF2, U2AF1 (synonym U2AF35), ZRSR2, and, as described previously, SF3B1, in the context of other molecular markers, including mutations in ASXL1, RUNX1, NRAS, TP53, IDH1, IDH2, NPM1, and DNMT3A. Mutations in SRSF2, U2AF1, ZRSR2, and SF3B1 were found in 24 (12.4%), 14 (7.3%), 6 (3.1%), and 28 (14.5%) patients, respectively, corresponding to a total of 67 of 193 MDS patients (34.7%). SRSF2 mutations were associated with RUNX1 (P < .001) and IDH1 (P = .013) mutations, whereas U2AF1 mutations were associated with ASXL1 (P = .005) and DNMT3A (P = .004) mutations. In univariate analysis, mutated SRSF2 predicted shorter overall survival and more frequent acute myeloid leukemia progression compared with wild-type SRSF2, whereas mutated U2AF1, ZRSR2, and SF3B1 had no impact on patient outcome. In multivariate analysis, SRSF2 remained an independent poor risk marker for overall survival (hazard ratio = 2.3; 95% confidence interval, 1.28-4.13; P = .017) and acute myeloid leukemia progression (hazard ratio = 2.83; 95% confidence interval, 1.31-6.12; P = .008). These results show a negative prognostic impact of SRSF2 mutations in MDS. SRSF2 mutations may become useful for clinical risk stratification and treatment decisions in the future.

2015 ◽  
Vol 33 (18) ◽  
pp. 2072-2083 ◽  
Author(s):  
Rosemary E. Gale ◽  
Katarina Lamb ◽  
Christopher Allen ◽  
Dima El-Sharkawi ◽  
Cassandra Stowe ◽  
...  

Purpose To evaluate the impact of DNMT3A mutations on outcome in younger patients with cytogenetic intermediate-risk acute myeloid leukemia. Patients and Methods Diagnostic samples from 914 patients (97% < 60 years old) were screened for mutations in DNMT3A exons 13 to 23. Clinical outcome was evaluated according to presence or absence of a mutation and stratified according to type of mutation (R882, non-R882 missense, or truncation). Results DNMT3A mutations (DNMT3AMUT) were identified in 272 patients (30%) and associated with a poorer prognosis than wild-type DNMT3A, but the difference was only seen when the results were stratified according to NPM1 genotype. This example of Simpson's paradox results from the high coincidence of DNMT3A and NPM1 mutations (80% of patients with DNMT3AMUT had NPM1 mutations), where the two mutations have opposing prognostic impact. In the stratified analyses, relapse in patients with DNMT3AMUT was higher (hazard ratio, 1.35; 95% CI, 1.07 to 1.72; P = .01), and overall survival was lower (hazard ratio, 1.37; 95% CI, 1.12 to 1.87; P = .002). The impact of DNMT3AMUT did not differ according to NPM1 genotype (test for heterogeneity: relapse, P = .4; overall survival, P = .9). Further analysis according to the type of DNMT3A mutation indicated that outcome was comparable in patients with R882 and non-R882 missense mutants, whereas in those with truncation mutants, it was comparable to wild-type DNMT3A. Conclusion These data confirm that presence of a DNMT3A mutation should be considered as a poor-risk prognostic factor, irrespective of the NPM1 genotype, and suggest that further consideration should be given to the type of DNMT3A mutation.


2020 ◽  
pp. JCO.20.02308
Author(s):  
Charles Craddock ◽  
Aimee Jackson ◽  
Justin Loke ◽  
Shamyla Siddique ◽  
Andrea Hodgkinson ◽  
...  

PURPOSE Reduced-intensity conditioning (RIC) regimens have extended the curative potential of allogeneic stem-cell transplantation to older adults with high-risk acute myeloid leukemia (AML) and myelodysplasia (MDS) but are associated with a high risk of disease relapse. Strategies to reduce recurrence are urgently required. Registry data have demonstrated improved outcomes using a sequential transplant regimen, fludarabine/amsacrine/cytarabine-busulphan (FLAMSA-Bu), but the impact of this intensified conditioning regimen has not been studied in randomized trials. PATIENTS AND METHODS Two hundred forty-four patients (median age, 59 years) with high-risk AML (n = 164) or MDS (n = 80) were randomly assigned 1:1 to a fludarabine-based RIC regimen or FLAMSA-Bu. Pretransplant measurable residual disease (MRD) was monitored by flow cytometry (MFC-MRD) and correlated with outcome. RESULTS There was no difference in 2-year overall survival (hazard ratio 1.05 [85% CI, 0.80 to 1.38] P = .81) or cumulative incidence of relapse (CIR) (hazard ratio 0.94 [95%CI, 0.60 to 1.46] P = .81) between the control and FLAMSA-Bu arms. Detectable pretransplant MFC-MRD was associated with an increased CIR (2-year CIR 41.0% v 20.0%, P = .01) in the overall trial cohort with a comparable prognostic impact when measured by an unsupervised analysis approach. There was no evidence of interaction between MRD status and conditioning regimen intensity for relapse or survival. Acquisition of full donor T-cell chimerism at 3 months abrogated the adverse impact of pretransplant MRD on CIR and overall survival. CONCLUSION The intensified RIC conditioning regimen, FLAMSA-Bu, did not improve outcomes in adults transplanted for high-risk AML or MDS regardless of pretransplant MRD status. Our data instead support the exploration of interventions with the ability to accelerate acquisition of full donor T-cell chimerism as a tractable strategy to improve outcomes in patients allografted for AML.


2019 ◽  
Vol 18 ◽  
pp. 153303381987392 ◽  
Author(s):  
Zhenjie Bai ◽  
Qingmei Yao ◽  
Zhongyi Sun ◽  
Fang Xu ◽  
Jicheng Zhou

Background: Despite diverse functions in diseases, the prognostic potential of the family of mitogen-activated protein kinase kinase kinase kinase genes in acute myeloid leukemia remains unknown. Methods: The messenger RNA expression of the MAP4K family members in 151 patients with acute myeloid leukemia was extracted from the OncoLnc database. Data for gender, age, cytogenetic, leukocyte count, CD34, FAB classification, RUNX1, and TP53 were provided by the University of California–Santa Cruz Xena platform. Kaplan-Meier analysis and Cox regression model provided an estimate of the hazard ratio with 95% confidence intervals for overall survival. Results: Analysis demonstrated favorable overall survival in patients with acute myeloid leukemia attributing to high expression of MAP4K3, MAP4K4, and MAP4K5 and low expression of MAP4K1 (adjusted P = .005, P = .022, P = .002, and P = .024; adjusted hazard ratio = 0.490, 95% confidence interval = 0.297-0.809, hazard ratio = 0.598, 95% confidence interval = 0.385-0.928, hazard ratio = 0.490, 95% confidence interval = 0.310-0.776, and hazard ratio = 0.615, 95% confidence interval = 0.403-0.938, respectively). Combining the high-expressing MAP4K3, MAP4K4, and MAP4K5 with the low-expressing MAP4K1 in a joint effect analysis predicted a favorable prognosis of overall survival in acute myeloid leukemia. Conclusion: High expression of MAP4K3, MAP4K4, and MAP4K5 combined with low expression of MAP4K1 can serve as a sensitive tool to predict favorable overall survival in patients with acute myeloid leukemia.


2009 ◽  
Vol 24 (1) ◽  
pp. 22-31 ◽  
Author(s):  
Samia Mourah ◽  
Raphaël Porcher ◽  
Géraldine Lescaille ◽  
Philippe Rousselot ◽  
Marie-Pierre Podgorniak ◽  
...  

Vascular endothelial growth factor (VEGF) and its receptors are known to play an important role in normal and pathological hematopoiesis but the prognostic impact of VEGF isoform transcripts in acute myeloid leukemia (AML) has not been addressed. We conducted a single-institution prospective study to analyze the impact of these angiogenic factors and the expression of their receptors on the survival of adult patients newly diagnosed with AML. We investigated the levels of VEGF transcript isoforms VEGF121, -145, -165, -189 and -206 and their receptors, VEGFR-1 and VEGFR-2, using quantitative reverse transcriptase polymerase chain reaction assays in peripheral blood mononuclear cells (PBMCs) of 67 consecutive AML patients at diagnosis. VEGF total protein was measured for comparison with mRNA levels in PBMCs. The VEGF121 splice variant transcript in AML PBMCs was significantly higher than in the normal controls. VEGF transcripts were quantified in all samples while its protein was detected in 42/67 (63%) of AML samples. High levels of VEGF121, VEGF165 transcripts and VEGF protein in AML were significantly related to a worse prognosis when analyzing overall survival (p<0.0001, p=0.019 and p=0.012, respectively) or event-free survival (p<0.0001, p=0.010 and p=0.047) using univariate analysis. In multivariable analysis only VEGF121 expression remained an independent prognostic factor for either event-free survival or overall survival [aHR=8.83 (3.48–22.4), p<0.0001, and aHR=9.52 (3.41–26.6), p<0.0001]. No prognostic value was observed for the other isoforms and the two receptors. Our findings show that the level of VEGF121 mRNA in circulating cells from AML patients is a strong independent prognostic parameter, which could be useful in the management of unselected AML patients.


Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4505-4511 ◽  
Author(s):  
Verena Ingeborg Gaidzik ◽  
Richard Friedrich Schlenk ◽  
Simone Moschny ◽  
Annegret Becker ◽  
Lars Bullinger ◽  
...  

AbstractTo evaluate the incidence and clinical impact of WT1 gene mutations in younger adult patients with cytogenetically normal acute myeloid leukemia (CN-AML), sequencing of the complete coding region was performed in diagnostic samples from 617 patients who were treated on 3 German-Austrian AML Study Group protocols. WT1 mutations were identified in 78 (12.6%) of the 617 patients; mutations clustered in exon 7 (54 of 78) and exon 9 (13 of 78), but also occurred in exons 1, 2, 3, and 8. WT1 mutations were significantly associated with younger age, higher serum lactate dehydrogenase levels, higher blood blast counts, and the additional presence of FLT3-ITD (P < .001) and CEBPA mutations (P = .004). There was no difference in relapse-free survival and overall survival between patients with (WT1mut) or without WT1 mutations. Subset analysis showed that patients with the genotype WT1mut/FLT3-ITDpos had a lower complete remission rate (P = .003) and an inferior relapse-free survival (P = .006) and overall survival (P < .001) compared with those with the genotype WT1mut/FLT3-ITDneg. In conclusion, in our large cohort of younger adults with CN-AML, WT1 mutation as a single molecular marker did not impact on outcome. However, our data suggest a negative impact of the genotype WT1mut/FLT3-ITDpos.


Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3563-3563
Author(s):  
Jee Hyun Kong ◽  
Hyun Ae Jung ◽  
Hee Kyung Ahn ◽  
Silvia Park ◽  
Hee-Jin Kim ◽  
...  

Abstract Abstract 3563 The distinctive features of the World Health organization (WHO) classification compared to French-America-British Co-operative group (FAB) classification of acute myeloid leukemia is the new morphological entity “AML with multilineage dysplasia (MLD)”, and now this subgroup has been renamed as 'AML with myelodysplasia-related change (MRC)”. It generally accepted that dysplasia was most frequently noted in older individual, is often associated with an unfavorable cytogenetic profiles and unfavourable response to therapy. However it is still controversial. Therefore, we evaluated the impact of MRC on overall survival (OS) and leukemia free survival (LFS) in acute myeloid leukemia patients. A total of 644 adult AML patients diagnosed at Samsung Medical Center (SMC) between Sep.1994 and Oct. 2010 were enrolled. We reviewed their medical histories, clinical parameters, hemogram data, bone marrow aspirate and cytogenetic studies, and reclassified them into AML with of MRC and without MRC groups. Of 664 patients, 543 patients were received induction chemotherapy, among them, 84 patients demonstrated MRC and 451 patients did not. Median age was 50 (15–88) years old, and 57.1% of patients were male. Median follow up period was 77.3 [0–191] months. AML without MRC group had more favorable cytogenetic risk, higher WBC counts and LDH levels than those with MRC. However, other variable such as age, sex, hemoglobin level, absolute neutrophil, and peripheral blast count, induction chemotherapy regimen, hematopoietic stem cell transplantation, CR1 (complete response after induction chemotherapy), CRp (complete recovery of platelet), and relapse rate were not different between two groups. Since FLT3-ITD and NPM1 tests were introduced into laboratory work after 2005, results of these tests were available only in 158 and 75 patients respectively, and these were not different between two groups. In univariate analysis, advanced age (>65 years) predicted worse LFS (median LFS [95% C.I.]; ° Â65 years vs >65 years; 9.3[7.2–11.4] vs 5.9[4.6–7.2] months, p =0.014). In terms of OS, young age (p=0.000), female (p=0.000), favorable cytogenetic risk (p=0.000), CR1 (p=0.000), CRp (p=0.000), absence of relapse (p=0.000), and HSCT (p=0.000) showed a higher probability of longer OS (Table 1). The presence of MRC, FLT3-ITD, and NPM1 did not affect OS (Table 1).Table 1.Summary of univariate analysis for overall survival.Median OS (months) [95% C.I.] or mean OS ± SD (months)pAge°Â65 years47.9 [17.1 – 78.6]0.000>65 years13.1 [5.9 – 20.4]SexMale23.2 [16.5 – 30.0]0.000¢Female112.2 [ – ]Cytogenetic risk¢Favorable107.0±7.40.000Intermediate28.0 [19.0 – 36.9]Unfavorable10.8 [7.8 – 13.7]Unknown17.5 [6.8 – 28.1]MRCAbsence35.9 [6.6 – 65.2]0.081Presence19.0 [6.9 – 31.0]CR1¢Yes112.2 [–]0.000No3.6 [1.1 – 6.1]CRp¢Yes70.9±4.40.000No54.8 [18.5 – 91.1]RelapseYes21.5 [17.2 – 25.9]0.000No17.5 [–]HSCT¢Auto86.2±5.60.000¢Allo83.8±6.5Not done17.5 [10.8 – 24.1]FLT3-ITDPositive8.2 [0–26.1]0.595Negative29.5 [20.9–38]NPM1¢Positive104.1±11.00.978¢Negative78.9±15.0¢“median survival not reached Next, we analyzed MRC effect in each variable to OS. The presence MRC did not affect OS of each group which divided according to the age (Figure 1. A and B), sex, cytogenetic risk groups (Figure 1. C and D), relapse, CR1, HSCT, and FLT3-ITD, though AML with MRC group had tendancy to have poor survival rate in intermediate cytogenetic risk group (Figure 1. C). However in patients who did not acheived CRp or showed NPM1, the presence of MRC correlated with shorter OS.Figure 1.Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D).Figure 1. Overall survival (OS) according to the presence of MRC in age ° Â65 group (A), age>65 group (B), intermediate cytogenetic risk group (C)), and unfavorable cytogenetic risk group (D). In this study, patients with MRC did not show inferior outcomes than those without MRC. Therefore it is not necessary to decide different treatment strategy according to the presence of MRC Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2594-2594
Author(s):  
Mario Annunziata ◽  
Piera Angelillo ◽  
Laura Vicari ◽  
Clelia Criscuolo ◽  
Felicetto Ferrara

Abstract Abstract 2594 Background: Abnormalities affecting long arm of chromosome 3 are rare but recurrent in Acute Myeloid Leukemia (AML) and are detected in a variable percentage of AML patients according to different series. The 2008 World Health Organization classification recognizes AML with inv(3)(q21q26.2) or t(3;3)(q21;q26.2) as a distinct subtype characterized by a poor prognosis. Allogeneic stem cell transplantation seems to improve outcome in eligible patients with these aberrations. Inappropriate expression of the ecotropic viral integration site 1 (EVI1) was demonstrated in virtually all patients with t(3;3)(q21;q26.2) and inv(3)(q21q26.2); as well as in a majority of patients with other 3q26 rearrangements. Other chromosome 3 abnormalities are rarely recognized in AML patients; clinical and prognostic relevance of these alterations is not yet defined. The aim of this study is to assess the prognostic impact of chromosome 3 abnormalities on disease characteristics and treatment outcome in AML. Patients and methods: A total of 580 consecutive adult patients were diagnosed with AML at our institution between February 2002 and July 2012. Conventional cytogenetic analysis performed on diagnostic bone marrow samples detected the presence of 3q abnormalities in 16 patients (2.7%). Two patients were lost to follow-up and were not evaluated for survival analysis. Molecular status of FLT3 and NPM1 was also performed and results are available for 10 patients. Median follow-up time for patients in this series was 47 months ( range 6–125). Results: There were 10 male and 6 female patients, the median age being 64.5 years (range 33–81), 10 patients had de novo AML while 6 evolved from a previously diagnosed myelodysplastic syndrome (MDS). Karyotype from MDS phase was available in 2 patients; both acquired 3q rearrangement at time of progression to AML. At time of diagnosis median haemoglobin value was 9.0 g/dL (range 4–11); median leucocyte count was 10.5 × 103̂/L (range 2.3 – 431). Median platelet count was 116 × 109̂/L (range 28 – 529), consistently with previous studies, which have shown that these patients present with higher platelet count at diagnosis when compared with no 3q rearranged ones. Regarding cytogenetic features 3 patients had t(3;3)(q21;q26), 3 patients had inv(3) (q21; q26), 3 patients showed a balanced rearrangement involving 3q26, while 6 patients harbored a del3q. One patient showed monosomy 3. Additional chromosomal changes were demonstrated in 5 patients, two of them had a complex karyotype (see Table 1), 3 had a monosomy 7. Thirteen patients out of 14 received intensive induction chemotherapy; complete remission (CR) was achieved in 5 patients (CR rate: 35.7%), the remaining 7 patients were resistant to induction as well as to salvage chemotherapy. Four patients underwent autologous stem cell transplantation. Median overall survival in this series is 5.5 months (range 0 – 20). At present only one patient is still alive and in CR, 20 months after diagnosis. Median disease free survival (DFS) for patients achieving a CR was 9 months (range 6–20). Median overall survival for patients resistant to first-line therapy was 3 months (range 0–6). Clinical features and treatment outcome of the patients are summarized in Table 1. Conclusions: The incidence of 3q abnormalities in our single institution series is 2.4%, in keeping with previous studies. Our findings confirm the association between these alterations and thrombocytosis at diagnosis, preceding MDS or multilineage dysplasia, presence in all FAB subtypes (except M3), association with additional chromosomal abnormalities as well as the poor response to conventional chemotherapy (CR rate 35.7%), and very short DFS in spite of obtaining CR. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2544-2544
Author(s):  
Xiuli Wang ◽  
Haiping Dai ◽  
Qian WANG ◽  
Qinrong Wang ◽  
Yang Xu ◽  
...  

Abstract Abstract 2544 Somatic mutation of the EZH2 gene is seen in myelodisplastic syndrome, myelofibrosis, and chronic myelomonocytic leukemia patients. The prevalence and prognostic impact of somatic mutations of EZH2 in patients with acute myelogenous leukemia (AML) remains unknown. In this study, we sought to determine the incidence and clinical implications of somatic EZH2 mutations in 714 patients with de novo AML by PCR amplification of the entire coding region followed by direct bidirectional DNA sequencing. EZH2 mutations were identified in 13/714 (1.8%) of AML patients and occurred almost exclusively in males (11/13, P=0.033). In univariate analysis, the presence of EZH2 mutations was significantly associated with lower blast percentage (21–30%) in bone marrow (P=0.0001) and −7/del(7q) (P=0.025). There was no difference in the incidence of mutations in 13 genes, including ASXL1, CBL, c-KIT, DNMT3A, FLT3, IDH1, IDH2, MLL, NPM1, NRAS, RUNX1, TET2, and WT1, between patients with and without EZH2 mutations. Complete remission, event-free survival or overall survival was similar between AML patients with and without EZH2 mutation (p>0.05). These results demonstrated EZH2 mutation as a recurrent genetic abnormality associated with lower blast percentage in BM and −7/del(7q) in de novo acute myeloid leukemia. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5256-5256
Author(s):  
Naresh Bumma ◽  
Jing Ai ◽  
Xuefei Jia ◽  
Sean Hobson ◽  
Donna Abounader ◽  
...  

Abstract Introduction: Lymphocyte recovery after induction chemotherapy (IC) predicts outcome in adult patients (pts) with acute myeloid leukemia (AML) (Behl et al. Leukemia 2006; 20: 29-34). However, it is unknown whether absolute lymphocyte count (ALC) recovery after IC predicts outcome in those pts who are then treated with allogeneic hematopoietic stem cell transplant (AHCT) in first complete remission (CR1). We hypothesized that the prognostic impact of ALC might be nullified by AHCT in CR1 due to the abrogation of normal immunologic recovery. In this study, our aims were to (1) evaluate the impact of Day 28 ALC on all AML pts receiving IC and (2) to specifically, evaluate the impact of Day 28 ALC on the subset of AML pts proceeding to AHCT in CR1. Methods: A retrospective chart review of 180 adult AML pts (≥ 18 years of age) who were treated with IC during the years 2001- 2012 at the Cleveland Clinic was performed. Institutional Review Board approval was obtained. Pts with acute promyelocytic leukemia were excluded . Ninety-four of the 180 pts received AHCT in CR1. A total of 141 AML pts receiving IC and a total of 66 pts receiving IC and then receiving AHCT in CR1 were eligible for data analysis because Day 28 ALC was missing in the remainder of the pts. Prior studies in AML identified an ALC of < 500/ µL at Day 28 of IC as predictive of overall survival. We stratified Day 28 ALC into the following categories: (a)< 250/ µL (b) < 350/ µL (c) < 500/ µL and (d) < 500/ µL for Max ALC [Max ALC was defined as the maximum ALC value between days 26 and 30 after the initiation of IC]. Other variables collected included age at diagnosis, WBC at diagnosis, and cytogenetic (CG) risk. CG risk was ascribed by CALBG criteria. The Kaplan-Meier method was used to summarize overall survival (OS) and relapse-free survival (RFS), which were measured for all pts from the time of diagnosis. The log-rank test was used for univariate analysis of categorical factors and the Cox proportional hazards model was used for measured factors and multivariate analysis. We performed two separate analyses : one for all AML pts (n=141); and a second analysis only focusing on those receiving AHCT in CR1 (n=66). Results: Pt characteristics for the entire AML cohort: The median age was 58.0 years (20.0-80.0); 46.1% female. The median WBC at diagnosis was 11.6 K / µL (range 0.7-220.7) and median Day 28 ALC was 400/ µL (0-2.4). Twenty-seven pts (19.7%) had favorable CG, 84 (61.3%) intermediate, and 26 (19.0%) unfavorable. Most pts (91%) received "7+3" IC and 93 (66%) also received at least 1 cycle of post-remission chemotherapy. On univariate analysis, age ≥60 (HR 2.72, p< 0.001), CG risk (HR 2.13, p < 0.001), Day 28 ALC < 250/ µL (HR 1.60, p=0.022), Day 28 ALC < 350/ µL (HR 1.57, p=0.029), and max ALC < 500/ µL (HR 1.54, p=0.035) were associated with a worse OS from the initiation of treatment. Low ALC was associated with both a higher incidence of refractory disease and death during induction (p=0.015). In our second analysis of pts undergoing AHCT in CR1, although not statistically significant, max ALC < 500/ µL (during IC) was associated with a trend towards decreased OS from the start of treatment on both univariate (HR 1.88,p= 0.13) and multivariate (HR 2.16, p=0.075) analysis. Conclusions: Max ALC < 500/ µL is predictive of outcome in AML pts undergoing IC, and there is a suggestion that this effect may not be abrogated by AHCT. A larger study will be needed to further confirm these findings. Therapies to improve lymphocyte recovery may be important in the treatment of AML. Disclosures Sekeres: Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees.


Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5613-5621 ◽  
Author(s):  
Sylvie M. Noordermeer ◽  
Mathijs A. Sanders ◽  
Christian Gilissen ◽  
Evelyn Tönnissen ◽  
Adrian van der Heijden ◽  
...  

Abstract Aberrations in protein ubiquitination have recently been identified in the pathogenesis of acute myeloid leukemia (AML). We studied whether expression changes of more than 1600 ubiquitination related genes correlated with clinical outcome in 525 adult AML patients. High expression of one of these genes, BRE, was observed in 3% of the cases and predicted favorable prognosis independently of known prognostic factors (5-year overall survival: 57%). Remarkably, unsupervised expression profiling showed that 86% of high BRE-expressing patients were confined to a previously unrecognized cluster. High BRE expression was mutually exclusive with FLT3 ITD, CEBPA, IDH1, and IDH2 mutations, EVI1 overexpression, and favorable karyotypes. In contrast, high BRE expression co-occurred strongly with FAB M5 morphology and MLL-AF9 fusions. Within the group of MLL-AF9–positive patients, high BRE expression predicted superior survival, while normal BRE expression predicted extremely poor survival (5-year overall survival of 80% vs 0%, respectively, P = .0002). Both the co-occurrence of high BRE expression with MLL-AF9 and its prognostic impact were confirmed in an independent cohort of 436 AML patients. Thus, high BRE expression defines a novel subtype of adult AML characterized by a favorable prognosis. This work contributes to improved risk stratification in AML, especially among MLL-AF9–positive patients.


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