High P53 Protein Expression Level Independent of Mutational Status Is An Adverse Prognostic Factor for Survival in Acute Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1490-1490 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Yi Hua Qiu ◽  
Sean Post ◽  
Steven M. Kornblau
Keyword(s):  
Overall Survival ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
P53 Protein ◽  
P53 Mutations ◽  
P53 Expression ◽  
The Poor ◽  
P53 Protein Expression ◽  
Mutational Status ◽  
Acute Myeloid

Abstract Abstract 1490 Background: The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML). In AML, p53 mutations have been associated with poor risk cytogenetics (i.e. complex karyotype, −5/−7). However, the function of p53 can also be compromised by protein stabilization and/or expression. The implications of p53 protein expression have not been studied in AML. Methodology: We assessed p53 expression by high-throughput reverse phase protein array (RPPA) technology in 511 pts (719 samples). Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1: 2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status was determined by Sanger sequencing of exons 5 through 9 of the p53 gene. Results: Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). Cases of AML-M3 and –M6 exhibited higher expression of p53 than other FAB subtypes. p53 expression directly correlated with age (p=0.01) and CD34 (p=0.001) and inversely correlated with WBC (p=0.007), BM (p=0.0001) and PB (p=0.0001) blasts, platelets (p=0.007), HLA-DR (p=0.01), CD19 (p=0.02), and survival (p=0.01). High p53 (p53high) expression level was more associated with unfavorable cytogenetics than with favorable or intermediate cytogenetics (p=0.00001). When all cytogenetic abnormalities were considered, pts with −5 had the highest levels of p53 (p=0.00001). Pts with RAS mutations, but not those with FLT3-ITD, NPM1, or IDH1/2, had lower levels of p53 protein. When pts were divided according to the level of p53 protein expression p53high was associated with lower complete remission (CR) rates (51% vs 56%; p=??) and higher relapsed rates (82% vs 62%; p=??). The median overall survival (OS) of pts with p53high and p53low were 29.8 vs. 51 wks (p=0.009). Most cases with p53high had unfavorable cytogenetics and the effect on OS was predominantly seen in that subpopulation with p53high and p53low pts living a medina of 23.4 vs. 36 wks (p=0.07), respectively. In order to determine whether the poor outcomes associated with p53high were due to the presence of a higher rate of p53 mutations among pts with p53high, we determined the p53 mutational status of 55 pts. p53high was highly correlated with the presence of p53 mutations as the latter were detected in 17/40 pts with p53high but in only 1/16 pts with p53low. Importantly, the presence of p53high, both in the presence (29 wks) or in the absence (24 wks) of p53 mutations, was associated with significantly worse overall survival compared with pts with p53low (56 wks; p=0.05, Figure 1). Multivariate analysis indicated that p53 is a significant independent risk factor for survival in AML. The final model included: age (p=0.000001), favorable cytogenetics (0.01), unfavorable cytogenetics (p=0.00001), WBC (p=0.0005), albumin (p=0.0003), FLT3-ITD (P=0.04), and P53 (P=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), c-MET (p=0.01), FoxO3a (p=0.004), KIT (p=0.001), p38p180p182 (p0.02), BAD (p=0.0001), cleaved PARP (p=0.002), cleaved PARP (p=0.01), TCF4 (p=0.02), fibronectin (p=0.02), and hsp70 (p=0.003), and negatively with AKTp473 (p=0.01), ERK (p=0.002), mTOR (p=0.005), PI3Kp85 (p=0.002), PKCδ (p=0.00002), GAB2 (p=0.00005), beclin (p=0.007), JMJD6 (p=0.001), Gata3 (p=0.02), p21 (p=0.01), and Mdm2 (p=0.001). Conclusions: Our results suggest that high levels of p53 protein constitute a powerful marker of short survival in AML. This effect is independent of p53 mutational status. The poor outcome of pts with high level of expression of p53 in the absence of p53 mutations suggests that the p53 pathway may be functionally perturbed in a much higher proportion of pts with AML than previously recognized. These data support the use of p53 protein expression levels in prognostication and in the development of targeted therapeutics. Disclosures: No relevant conflicts of interest to declare.

High p53 Protein Expression LEVEL Independent Of Mutational Status Is An Adverse Prognostic Factor For Survival In ACUTE Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1330-1330
Author(s):  
Alfonso Quintas-Cardama ◽  
Sean M. Post ◽  
Kensuke Kojima ◽  
Yi Hua Qiu ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
P53 Pathway ◽  
P53 Expression ◽  
Mutational Status ◽  
Wild Type P53 ◽  
Acute Myeloid

Abstract Background The tumor suppressor p53 is frequently mutated in human cancer, including acute myeloid leukemia (AML), particularly in cases with high-risk cytogenetics. It has been shown that p53 stabilization, which frequently occurs when the protein is mutated, can compromise its function. We have shown that p53 stabilization, regardless of the presence of mutations, suggesting alterations of other components in the p53 pathway. Methodology p53 expression was determined using high-throughput reverse phase protein array (RPPA) technology in 719 samples from 511 pts. Eleven CD34+ bone marrow (BM) and 10 normal peripheral blood (PB) lymphocyte samples were used as controls. Samples were printed as 5 serial 1:2 dilutions in duplicate using an Aushon 2470 Arrayer. Mutational status of p53 alleles was assessed by Sanger sequencing of exons 5 through 9. Expression of components of the p53 pathway was determined using standard immunohistochemical techniques. Nutlin-3a was used in in vitro culture experiments. Results Paired PB- and BM-derived AML samples expressed similar p53 levels (p=0.25). A trend towards higher p53 expression at relapsed was observed among 47 paired diagnosis/relapse samples (p=0.07). p53 expression correlated directly with CD34 (p=0.001) and inversely correlated with WBC (p=0.007), PB and BM blast burden (p=0.0001), and survival (p=0.01). High p53 (p53high) expression was more associated with unfavorable cytogenetics, particularly -5 (p=0.00001). p53high resulted in lower complete remission (CR) rates (51% vs 56%; p=??), higher relapsed rates (82% vs 62%; p=??), and shorter median overall survival (OS; 29.8 vs. 51 wks, p=0.009) compared to p53low pts. Most cases with p53high had unfavorable cytogenetics. We next correlated p53 stabilization with the presence of p53 mutations in 68 pts. p53 mutations were detected in 20/54 (37%) p53high pts and in 0/14 (0%) pts with p53low. p53high, either in the presence (29 wks) or in the absence (24 wks) of p53 mutations (p=1.0), was associated with significantly shorter OS compared with p53low pts (56 wks; p=0.05). Multivariate analysis revealed p53 expression to be an independent risk factor for survival in AML (p=0.02). p53high was positively correlated with p53pSER15 (p=0.00001), Rbp807p811 (p=0.0002), BAD (p=0.0001), cleaved PARP (p=0.002), and cleaved PARP (p=0.01), and negatively with p21 (p=0.01), and MDM2 (p=0.001).Given the similar OS in p53high pts carrying mutant or wild-type p53, we scored the immunohistochemical expression of MDM2, MDM4, and p21 in 30 p53high pts (9 p53 mutated, 21 wild-type p53). Overexpression of MDM2 was observed in 44% vs 48% pts with mutant vs wild-type p53, respectively, whereas rates were 67% vs 62% for MDM4, and 0% vs 19% for p21, for each respective genotype. Overall, of the 21 p53high pts carrying wild-type p53, 15 (71%) had overexpression of MDM2 and/or MDM4, whereas 81% had no p21 expression, indicating deficient activation of the p53 pathway similar to those cases carrying mutant p53. We are currently assessing response to nutlin-3a therapy in 24 primary AML samples (4 mutant p53, 20 wild-type p53). Results showing the impact of p53 mutation and/or stabilization, and expression levels of MDM2, MDM4, and p21 on nutlin-3a therapy will be presented. Conclusions p53 stabilization (p53high) is a powerful predictive and prognostic factor in AML, which is independent of the presence of mutant p53 alleles. Poor outcomes in pts with p53high lacking p53 mutations are very frequently associated with overexpression of negative regulators of p53 such as MDM2 and/or MDM4 and p21 downregulation, indicating a functionally altered p53 pathway. These findings may have implications for therapies targeting the MDM2/p53 axis in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Prognostic Impact of the Interaction between DNMT3A mutation and Internal Tandem Duplication of the FLT3 Gene (FLT3-ITD) in Patients with De Novo Mutated NPM1 (NPM1mut) acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1492-1492
Author(s):  
Guadalupe Oñate ◽  
Ana Garrido ◽  
Jordi Esteve ◽  
Rosa Coll ◽  
Montserrat Arnan Sangerman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Mutational Status ◽  
De Novo Aml ◽  
Acute Myeloid

Abstract Introduction The association of NPM1mut and FLT3-ITD in de novo acute myeloid leukemia (AML) with intermediate-risk cytogenetics has different prognostic impact depending on the FLT3 allelic burden. Previous studies published by our cooperative group showed that patients with de novo AML of intermediate-risk cytogenetics with NPM1mut and FLT3-ITD low ratio (<0.5, FLT3low) at diagnosis presented an overall survival and relapse rate similar to those with NPM1mut and FLT3wt. Therefore, in the CETLAM-2012 protocol, patients with FLT3low NPM1mut AML are not considered for allogenic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1). Recent studies suggest that the co-occurrence of DNMT3A mutation in FLT3-ITD NPM1mut AML patients confers a worse prognosis regardless of FLT3-ITD ratio. We analysed our data to determine whether these findings were confirmed in our cohort, specifically in the low FLT3-ITD ratio patients, since this could have therapeutic implications. Methods and patients A total of 163 patients with de novo AML, intermediate-risk cytogenetics and NPM1mut were analysed (median age 53 years (18-72); male:female 72:91 (0.79)). Eighty patients (49%) harboured an FLT3-ITD, with a high allelic ratio in 42 of 76 patients with available ITD/wt ratio (55%). They were included in the AML-2003 (n=49) and AML-2012 (n=114) CETLAM protocols. Proportion of patients undergoing alloHSCT in CR1 is detailed in table 1. Bone marrow samples from diagnosis were studied for DNMT3A mutations as previously described. The definition of complete remission (CR), overall survival (OS), leukemia-free survival (LFS) and risk of relapse (RR) followed recommended ELN criteria. The Kaplan-Meier method was used to estimate the distribution of LFS and OS, for RR cumulative incidence was used. Results Out of the 163 patients with AML of intermediate risk cytogenetics and NPM1mut, 78 presented DNMT3A mutations (48%). Of these, 62 (79%) presented mutations in codon R882 or corresponded to DNA insertions/deletions while 16 (21%) harboured missense mutations. Presence of DNMT3A mutation did not associate with FLT3-ITD (ITD/85 DNMT3Awt vs ITD/78 DNMT3Amut, p=0.394). In the entire cohort, 5-year OS, LFS and RR were 58±4.5%, 59±4.6% and 27±13.9%. FLT3-ITD ratio confirmed its prognostic impact when analysing FLT3wt (n=83) vs FLT3low (n=34) vs FLT3high (n=42) patients (5-year OS of 68±6% vs 62±8.7% vs 37±8.6%; p=0.002; and 5-year RR of 18±9.4% vs 27±16.1% vs 41±23.2%; p=0.023). On the contrary, DNMT3Amut did not exert any effect on overall outcome (5-yr OS DNMT3Awt vs DNMT3Amut 61±6.2% vs 55±6.2%; p=0.234) When DNTM3A mutational status was considered, the impact of FLT3-ITD on outcome was mitigated in wild-type DNMT3A population. Thus, we found that DNMT3Awt patients presented no statistical differences in OS according to FLT3 mutational status or ratio: FLT3wt (n=46) vs FLT3-ITD (n=39) was 67±8.5% vs 57±8.2%; p=0.122, whereas FLT3wt (n=46) vs FLT3low (n=18) vs. FLT3high (n=19) was 67±8.5% vs. 66±11.5% vs 46±11.8%; p=0.088 (image 1A).This was also seen in relation to LFS and RR according to FLT3 ratio: 5-yr LFS of FLT3wt vs FLT3low vs FLT3high was 72±7.9% vs 61±12.6% vs 51±13.4%; p=0.244 and 5-year RR of the same groups: 19±8.8% vs 26±12.5% vs 27±21.9%; p=0.724 (image 2A). In the DNMT3Amut group, patients with FLT3-ITD (n=41) presented shorter OS than those with FLT3wt (n=37) with an OS of 37±10.7% vs 69±7.8%; p=0.028. When FLT3 ratio was considered, FLT3wt (n=37) vs FLT3low (n=16) vs FLT3high (n=23) showed an OS of 69±7.8% vs. 58±13.2% vs 27±13.1%; p=0.038 (image 1B). Similar results were seen in LFS according to FLT3 ratio (FLT3wt (n=29) vs FLT3low (n=16) vs FLT3high (n=20) 71±8.6% vs 53±12.9% vs 18±13.8%; p=0.012). Finally, we observed significant differences in the 5-year RR when considering DNMT3Amut patients in relation to FLT3 ratio (FLT3wt vs FLT3low vs FLT3high 18±10.6% vs 27±20% vs 54±28.8%; p=0.021)(image 2B). Conclusions In this study, patients with NPM1mut and FLT3-ITDlow presented a similar outcome to patients with NPM1mut and FLT3wt regardless of DNMT3A mutational status. These results support the modification of alloHCST policy in CR1 in CETLAM-2012, which do not consider alloHSCT for patients with FLT3low. On the other hand, concurrence of DNMT3A mutation may have an added negative effect in patients with NPM1mut and FLT3-ITDhigh, which should be further confirmed in larger studies. Disclosures No relevant conflicts of interest to declare.

P53 expression as a predictor of recurrence in cervical squamous cell carcinoma

2002 ◽  
Vol 12 (3) ◽  
pp. 299-303 ◽  
Author(s):  
S. M. F Brenna ◽  
L. C Zeferino ◽  
G. A Pinto ◽  
R. A Souza ◽  
L. A. L Andrade ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
P53 Protein ◽  
Figo Stage ◽  
Cervical Squamous Cell Carcinoma ◽  
Stage Ii ◽  
P53 Expression ◽  
P53 Protein Expression

Abstract.Brenna SMF, Zeferino LC, Pinto GA, Souza RA, Andrade LAL, Vassalo J, Martinez EZ, Syrjänen KJ. P53 expression as a predictor of recurrence in cervical squamous cell carcinoma.P53 protein function is frequently down-regulated in cervical cancer by complexing with human papillomavirus (HPV) E6 protein, leading to degradation of p53, genomic instability, and mutations. Results are controversial, however, on the prognostic value of p53 protein expression in cervical cancer. In this study, a cohort of 220 Brazilian women with FIGO stage IB-III cervical squamous cell carcinoma (SCC), followed for 5 years, was analyzed for p53 protein expression using immunohistochemistry. The disease-free survival (DFS) and relapse rate were analyzed using univariate (Kaplan-Meier) and multivariable (Cox's proportional hazards model) survival analyses. P53 protein expression was detected in 35% of the patients, including 21% in stage I, 28% in stage II and 51% in stage III of disease. Of 220 women, only 116 completed one of the treatment options standardized by FIGO within 120 days. There was a higher risk of relapse in stage II and III disease, that was not modified by p53 positivity; HR 3.0 (1.3–6.5) to stage II and HR 4.0 (1.9–8.5) to stage III. The multivariate analysis evidenced that p53 expression is not an independent factor exceeding the power of FIGO stage as the single most important determinant of the hazards for disease relapse.

P53 Protein Expression Levels Are Prognostic in AML and Predict for Mutational Status.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2397-2397 ◽  
Author(s):  
Steven M. Kornblau ◽  
Joseph Barnett ◽  
YiHua Qiu ◽  
Wenjing Chen ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Protein Expression ◽  
P53 Protein ◽  
Leukemia Cell ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
P53 Expression ◽  
Mutation Status ◽  
Expression Levels ◽  
P53 Protein Expression ◽  
Very High

Abstract Mutation of the P53 gene in AML confers an adverse prognosis and is associated with unfavorable cytogenetics typically with complex karyoptyes. Since P53 function can also be modulated by MDM2 associated, ubiquitin dependent, destruction, the amount of P53 protein may also be relevant to leukemia blast biology. Previous studies have focused on the presence or absence of mutations, but have not examined the relevance of protein expression levels. We evaluated the levels of expression of P53 using high-throughput reverse phase protein array technology (RPPA) on 537 leukemia cell enriched samples from 423 patients (258 newly diagnosed, 47 primary refractory, 118 relapse 1, 2 or refractory). Levels of P53 were lower, equal and higher than that of normal CD34+ cells in 57%, 37% and 16% of cases, respectively. Almost all cases with very high P53 had unfavorable cytogenetics with complex karyotypes (15/16 newly diagnosed), and very high P53 was observed in 13% of patients with unfavorable cytogenetics compared to &lt;1% with favorable or intermediate cytogenetics. Changes involving chromosome 5 (66% vs. 9%) and 7 (50% vs. 11%) were very common in those with very high P53 compared to those with normal or low P53. Levels of expression were similar regardless of disease status; newly diagnosed, primary refractory or relapsed We tested the hypothesis that patients with very high P53 were likely to have mutations by performing RT-PCR sequencing, covering exons 5–9 in 23 very high, and 11 low P53 expressing patients. Among very high expressers 11 missense mutations were found in 9 patients (39% overall), including 7 of 13 newly diagnosed cases (54%) compared to 0 of 11 low expressers (p=0.02 all cases, 0.05 newly diagnosed). Mutations occurred at known hot spots: including 5 in exon 8 [3 at codon 273], 3 in exon 7 and 2 in exon 5 and 6. High P53 expression was inversely correlated with PTEN expression (P=0.001, see accompanying abstract). Expression was unaffected by FLT3-ITD mutation status. For outcome analysis, martingale residuals were utilized to define an optimal cutpoint for dichotomization into groups with Higher (n=57, 50 treated) vs. lower (n=201, 165 treated) P53. Patients with higher P53 were significantly more likely to have an antecedent hematological disorder (37% vs. 17%, P=0.002) and unfavorable cytogenetics (65% vs. 39%, P=0.0002). Response to therapy and outcome were significantly worse in those with higher P53. The complete remission rate was significantly lower in those with higher P53 (46% vs. 66%, P=0.01). The relapse rate was significantly higher (74% vs. 47%, P=0.02) and the median remission duration was significantly shorter (26 vs. 43 weeks, P=0.02). The combination resulted in a significantly shorter median survival (26 vs. 44 weeks, P=0.0003). Analysis of MDM2 expression in these same cases is underway. This data demonstrates that cases of AML with very high levels of P53 protein expression, measured by RPPA, are frequently found in those with P53 mutations. Not all patients with high P53 levels have mutations, but high levels of P53 protein carry an adverse prognosis, regardless of mutation status.

p53 Expression in B-Cell Chronic Lymphocytic Leukemia: A Marker of Disease Progression and Poor Prognosis

Blood ◽  
1998 ◽  
Vol 91 (11) ◽  
pp. 4342-4349 ◽  
Author(s):  
Iole Cordone ◽  
Serena Masi ◽  
Francesca Romana Mauro ◽  
Silvia Soddu ◽  
Ornella Morsilli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protein Expression ◽  
P53 Protein ◽  
Clinical Stage ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
P53 Expression ◽  
Short Survival ◽  
P53 Protein Expression ◽  
Cell Chronic Lymphocytic Leukemia

We have analyzed by immunocytochemistry (ICC) the frequency of p53 protein expression in 181 cases of B-cell chronic lymphocytic leukemia (CLL) followed at a single institution to assess the relationship between p53 and the clinical and morphological features of the disease, as well as the possible involvement of this protein in the pathogenesis of the more aggressive forms of CLL. The overall frequency of p53 protein positivity in CLL was 15% (27 of 181 cases). There were no significant differences in age, sex, absolute lymphocyte count, or lymphocyte doubling time between p53-positive and -negative patients. By contrast, p53-positive patients had a significantly higher percentage of prolymphocytes (P = .002) and a significantly lower percentage of residual CD3-positive T lymphocytes (P = .0001). No correlation was found between the percentage of p53-positive cells and the percentage of cells in cycle assessed by the monoclonal antibody Ki-67. When the percentage of p53 positivity was correlated with the clinical stage of the disease, the proportion of p53-positive cases increased significantly from Binet's stage A (8 of 108; 7.4%), to stage B (12 of 49; 24.4%) and C (7 of 24; 29.2%) (P = .002). p53 positivity correlated also with the phase of the disease, showing a low expression at diagnosis (8 of 112; 7.1%) and a significantly higher expression in patients studied during the course of the disease (7 of 35; 20%) and, to a further extent, with disease progression (12 of 34; 35.3%) (P = .0001). The association of p53 protein expression with mutations in the gene was confirmed by direct sequence of the entire cDNA in 15 of the 17 ICC positive cases tested (88%). A significantly shorter treatment-free interval from diagnosis (P = .003) and a poorer response to therapy (P = .007) was observed in p53-positive compared with p53-negative patients. Overall survival from the time of diagnosis, as well as from the time of p53 protein analysis, was significantly shorter in patients with p53 protein expression (P = .03 and .0001, respectively). Moreover, in multivariate analysis, p53 expression and stage C were independently associated with a short survival. The results of this study indicate that in CLL the expression of the p53 protein, analyzed by a simple and reliable immunocytochemical method, is strongly associated with p53 gene mutations, a morphological variant (CLL with >10% prolymphocytes), advanced clinical stage, progressive disease, poor response to therapy, and short survival.

scholarly journals An IDO1-related immune gene signature predicts overall survival in acute myeloid leukemia

2021 ◽  
Author(s):  
Simone Ragaini ◽  
Sarah Wagner ◽  
Giovanni Marconi ◽  
Sarah Parisi ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Prognostic Significance ◽  
Gene Signature ◽  
Immune Gene ◽  
Immune Biomarkers ◽  
Mutational Status ◽  
Acute Myeloid

The contribution of the bone marrow (BM) immune microenvironment (TME) to acute myeloid leukemia (AML) development is well-known, but its prognostic significance is still elusive. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is an interferon (IFN)-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 732 patients with newly diagnosed, non-promyelocytic AML were retrieved from public datasets and analyzed using established computational pipelines. Targeted transcriptomic profiles of 24 diagnostic BM samples were analyzed using the NanoString's nCounter platform. BIN1 and IDO1 were inversely correlated and individually predicted overall survival. PLXNC1, a semaphorin receptor involved in inflammation and immune response, was the IDO1-interacting gene retaining the strongest prognostic value. The incorporation of PLXNC1 into the 2-gene IDO1-BIN1 score gave rise to a powerful immune gene signature predicting survival, especially in patients receiving chemotherapy. The top differentially expressed genes between IDO1low and IDO-1high and between PLXNC1low and PLXNC1 high cases further improved the prognostic value of IDO1 providing a 7 and 10-gene immune signature, highly predictive of survival and correlating with AML mutational status at diagnosis. Taken together, our data indicate that IDO1 is pivotal for the construction of an immune gene signature predictive of survival in AML patients. Given the emerging role of immunotherapies for AML, our findings support the incorporation of immune biomarkers into current AML classification and prognostication algorithms.

Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study.

1996 ◽  
Vol 14 (7) ◽  
pp. 2131-2138 ◽  
Author(s):  
M H Kramer ◽  
J Hermans ◽  
J Parker ◽  
A D Krol ◽  
J C Kluin-Nelemans ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lymphoma ◽  
P53 Protein ◽  
B Cell Lymphoma ◽  
Population Based ◽  
Clinical Factors ◽  
P53 Expression ◽  
P53 Protein Expression ◽  
Large B Cell Lymphoma ◽  
Bcl2 Protein

PURPOSE We studied the prognostic significance of bcl2 and p53 protein expression in relation to clinical and pathologic characteristics in patients with diffuse large B-cell lymphoma (LCL). PATIENTS AND METHODS Three hundred seventy-two patients with LCL were retrieved from a population-based registry for non-Hodgkin's lymphoma (NHL). bcl2 and p53 protein expression was studied on paraffin-embedded tumor tissue by immunohistochemistry in relation to clinical factors. Response to therapy and survival were analyzed in 165 patients who were uniformly staged and treated and for whom all prognostic data were available according to the International Prognostic Index (IPI). RESULTS Forty-five percent of tumors showed strong expression of the bcl2 protein (bcl2++), with a higher frequency in patients with primary nodal involvement. Disease-free survival (DFS) was significantly better in bcl2-negative/intermediate (bcl2-/+) cases as compared with bcl2++ cases (P = .0011). At 5 years, bcl2-/+ patients showed a DFS rate of 74%, in contrast to bcl2++ patients with a DFS rate of 41% (P = .002). Bcl2 was the strongest independent prognostic value in a multivariate analysis, with a relative risk (RR) of 3.0 in comparison to p53 expression and the clinical factors of the IPI. Overall survival (OS) was not significantly influenced by bcl2 protein expression. p53 protein expression was found in 13% of cases, with a higher frequency in patients with extensive disease. p53 expression did not influence the chance to achieve complete remission (CR) and survival. CONCLUSION bcl2 protein is frequently expressed in LCL and is a strong independent prognostic factor for DFS. p53 expression is related with high tumor burden, but is not an independent risk factor for CR and survival.

High levels of p53 protein expression do not correlate with p53 mutations in hepatocellular carcinoma

2004 ◽  
Vol 11 (6) ◽  
pp. 502-510 ◽  
Author(s):  
M. Anzola ◽  
A. Saiz ◽  
N. Cuevas ◽  
M. Lopez-Martinez ◽  
M. A. Martinez de Pancorbo ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Protein Expression ◽  
P53 Protein ◽  
P53 Mutations ◽  
P53 Protein Expression

Aberrant p53 protein expression and function in a panel of hematopoietic cell lines with different p53 mutations

2009 ◽  
Vol 82 (4) ◽  
pp. 301-307 ◽  
Author(s):  
Shimeru Kamihira ◽  
Chiharu Terada ◽  
Daisuke Sasaki ◽  
Katsunori Yanagihara ◽  
Kunihiro Tsukasaki ◽  
...  
Keyword(s):  
Protein Expression ◽  
Cell Lines ◽  
P53 Protein ◽  
Hematopoietic Cell ◽  
P53 Mutations ◽  
P53 Protein Expression ◽  
And Function ◽  
Hematopoietic Cell Lines

Implications of Gene and p53 Protein Alterations in Determining Progression of Chronic Myeloid Leukemia Phases.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4348-4348
Author(s):  
Geraldo Barroso Cavalcanti ◽  
Eliane Pereira ◽  
Marcos Antônio Mauricio Sheiner ◽  
Flavia da Cunha Vasconcelos ◽  
Claudete Esteves Klumb ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Protein Expression ◽  
Myeloid Leukemia ◽  
P53 Protein ◽  
Chronic Phase ◽  
Tp53 Gene ◽  
Genetic Alterations ◽  
Blastic Crisis ◽  
Important Indicator ◽  
P53 Protein Expression

Abstract TP53 gene and p53 protein play an important role in the control of the cell cycle and DNA repair. Alterations in the TP53 gene and in the p53 protein expression have been considered an unfavorable prognostic factor for certain forms of human cancer. Mutations in the TP53 gene in patients with chronic myeloid leukemia (CML) were found in up to 30 %, specially among those in blastic crisis. At present, the only widely available technology that reliable detects and defines all mutations is DNA sequencing. However, the routine of sequencing the entire TP53 gene, in all suggestive cases of mutation, in the laboratorial routine is prohibitively costly, complex, and time consuming. To screening of those genetic alterations for p53 protein expression and TP53 gene abnormalities, in CML patients, flow cytometry (FC) and single strand conformation polymorphism of polymerase chain reaction products (PCR-SSCP) techniques are proposed. We report the results of an analysis of 72 blood samples from CML patients: 54 in chronic phase (33 in initial chronic phase (ICP) and 21 in late chronic phase (LCP)), 7 in accelerated phase (AP) and 11 in blastic crisis (BC). DNA structure for exons 5, 6, 7, 8 and 8–9 of the TP53 gene and p53 protein expression using the monoclonal antibody DO7 by FC was performed. By PCR-SSCP analysis, shift in eletrophoretic mobility of the TP53 gene, were detected in 11 patients and p53 protein were expressed in 17 out of 72 CML patients. The abnormal PCR-SSCP pattern were showed in one case of ICP (exon 7), five cases of LCP (two in the exon 7, one in the exon 8 and two in the exons 8–9), one in AP (exon 8) and four in BC (two in the exon 5, one in the exon 6 and one in the exon 8–9). In these cases, the p53 protein were expressed in seven cases (in all cases of CB and AC and 2 out of 5 LCP samples of CML patients). The statistic analysis by qui-square test showed significance between the results of the two methods (p= 0,002). These results suggest that the two concomitant methods can increase the sensibility for screening the p53 protein expression and TP53 gene abnormalities in CML patients. The presence of abnormal profile of PCR-SSCP associated to the p53 protein expression, in advanced phases of this disease, might be considered an important indicator of the phase progression of CML.

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