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.

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

Abstract 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.

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 <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 protein expression in chronic lymphocytic leukemia

2012 ◽  
Vol 53 (7) ◽  
pp. 1282-1288 ◽  
Author(s):  
Ludger Sellmann ◽  
Alexander Carpinteiro ◽  
Holger Nückel ◽  
René Scholtysik ◽  
Dörte Siemer ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Protein Expression ◽  
P53 Protein ◽  
Lymphocytic Leukemia ◽  
P53 Protein Expression

scholarly journals Prognostic significance of immunoglobulin phenotype in B cell chronic lymphocytic leukemia

Blood ◽  
1985 ◽  
Vol 65 (2) ◽  
pp. 340-344 ◽  
Author(s):  
L Baldini ◽  
R Mozzana ◽  
A Cortelezzi ◽  
A Neri ◽  
F Radaelli ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Clinical Prognosis ◽  
Delta Type ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Seventy-six consecutive untreated patients with B cell chronic lymphocytic leukemia (B-CLL) and classified according to Binet's staging system were studied at the clinical presentation. Several immunologic parameters (number of total and T circulating lymphocytes and their surface membrane immunoglobulin [Smlg] phenotypes and levels of serum Ig) were evaluated with the aim of identifying a biologic marker of prognostic relevance. In this series of persons, Binet staging confirmed its usefulness as a prognostic index (P less than .001). With regard to Smlg, they were mu-type in 41 cases (53.9%), mu- type plus delta-type in 29 cases (38.2%), alpha-type in one case, and not detectable in five cases. No correlations were found between clinical stage and immunoglobulin phenotype, although all but one patient in stage C showed mu-type Smlg alone. On analyzing the survival curves of our patients according to different Smlg phenotypes, we found that patients with only mu-type Smlg had a poorer prognosis (P less than .05) than those with mu-type plus delta-type; this difference was even more significant (P less than .01) in patients in stage A, whereas there were no statistical differences in those in stages B and C. Because the appearance of surface heavy chain of delta-type could be an expression of cell maturation, these results suggest that in B-CLL the presence of phenotypically more mature leukemic cells may correlate with better clinical prognosis, particularly in the early phase of the disease.

scholarly journals Recombinant alpha 2-interferon in the treatment of B chronic lymphocytic leukemia in early stages

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1295-1298 ◽  
Author(s):  
C Rozman ◽  
E Montserrat ◽  
N Vinolas ◽  
A Urbano-Ispizua ◽  
JM Ribera ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Complete Response ◽  
Absolute Number ◽  
Peripheral Blood Lymphocytes ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Low Doses ◽  
The Absolute ◽  
Cell Chronic Lymphocytic Leukemia

Abstract Ten previously untreated patients with early B cell chronic lymphocytic leukemia (B-CLL) (seven in Rai's stage 0, three in stage I) were given recombinant alpha 2-interferon (alpha 2IF) (2 X 10(6) U/m2 intramuscularly three times a week for a minimum of 14 weeks) to assess its effectiveness. All patients were evaluable for response to therapy and toxicity. No complete response was achieved. In all cases a definite, although transient reduction in the absolute number of peripheral blood lymphocytes was observed. In eight patients an increase in the absolute number of granulocytes was detected. None of the patients experienced severe hematologic toxicity. Fatigue, malaise, and fever were the more common side effects, but all patients were able to finish their treatment as planned. The results of this pilot study suggest that low doses of recombinant alpha 2-IF have some activity in early and previously untreated B-CLL and that further studies of IF effectiveness in B-CLL seem warranted.

scholarly journals Recombinant alpha 2-interferon in the treatment of B chronic lymphocytic leukemia in early stages

Blood ◽  
1988 ◽  
Vol 71 (5) ◽  
pp. 1295-1298
Author(s):  
C Rozman ◽  
E Montserrat ◽  
N Vinolas ◽  
A Urbano-Ispizua ◽  
JM Ribera ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Complete Response ◽  
Absolute Number ◽  
Peripheral Blood Lymphocytes ◽  
Response To Therapy ◽  
Lymphocytic Leukemia ◽  
Hematologic Toxicity ◽  
Low Doses ◽  
The Absolute ◽  
Cell Chronic Lymphocytic Leukemia

Ten previously untreated patients with early B cell chronic lymphocytic leukemia (B-CLL) (seven in Rai's stage 0, three in stage I) were given recombinant alpha 2-interferon (alpha 2IF) (2 X 10(6) U/m2 intramuscularly three times a week for a minimum of 14 weeks) to assess its effectiveness. All patients were evaluable for response to therapy and toxicity. No complete response was achieved. In all cases a definite, although transient reduction in the absolute number of peripheral blood lymphocytes was observed. In eight patients an increase in the absolute number of granulocytes was detected. None of the patients experienced severe hematologic toxicity. Fatigue, malaise, and fever were the more common side effects, but all patients were able to finish their treatment as planned. The results of this pilot study suggest that low doses of recombinant alpha 2-IF have some activity in early and previously untreated B-CLL and that further studies of IF effectiveness in B-CLL seem warranted.

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.

A Prospective Study of Young Chronic Lymphocytic Leukemia (CLL) Patients Investigated at Diagnosis: Distribution and Clinical Significance of Prognostic Factors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3121-3121
Author(s):  
Ilaria Del Giudice ◽  
Francesca Romana Mauro ◽  
Maria Stefania De Propris ◽  
Simona Santangelo ◽  
Marilisa Marinelli ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
P53 Protein ◽  
Young Patients ◽  
P53 Gene ◽  
Lymphocytic Leukemia ◽  
Mutation Status ◽  
P53 Protein Expression ◽  
Binet Stage ◽  
Wbc Count

Abstract In chronic lymphocytic leukemia (CLL) the distribution and prognostic impact of genetic and molecular markers has been assessed on retrospective series of patients in different phases of the disease. Our aim was to assess the distribution and clinical significance of a comprehensive panel of clinical and biologic parameters prospectively evaluated at presentation in all young patients diagnosed with CLL at our Institution, taking advantage of the fact that in Italy individuals with a lymphocytosis are referred to the hematologist for the diagnostic work-up. From November 2002 to June 2008, 105 young CLL patients (<60 years-old) were diagnosed with CLL and included in this study. There were 56 males and 49 females, with a median age of 52 years-old. 81% were in Binet stage A, 19% in stages B/C. Rai stage 0 was recorded in 63% of patients, I/II in 31%, III/IV in 6%. The median white blood cell (WBC) count was 18.8 × 109/L (range 5.8–236.6). Prognosis was evaluated as the time from diagnosis to first treatment (TFI, treatment-free interval), since only 3 patients died after a median follow-up of 32.4 months (range 1 to 88). The median TFI was 43.9 months. Clinical features included: gender, WBC count, Binet and Rai stage. Serological and biologic parameters included: beta2-microglobulin, LDH, IgG immunoglobulin levels, lymphocyte morphology, T-cell subsets, IgVH mutational status, CD38 and ZAP-70 expression, cytogenetic abnormalities evaluated by FISH, p53 protein expression and p53 gene sequencing (exon 5 to 8). The distribution of the prognostic markers is summarized in the table. Raised beta2-microglobulin and LDH were present only in 5% and 15% of cases, respectively. The CD4/CD8 ratio was normal in almost all cases. The proportion of unmutated IgVH, CD38 and ZAP-70 positive cases was about one third of the cohort of CLL patients at diagnosis. The incidence of del(17p) (cut off >20% cells) and del(11q) (cut off >10% cells) was 2% and 7%, respectively. Patients with del(17p) or del(11q) exclusively showed unmutated IgVH and ZAP-70+, and were mostly CD38+. p53 mutations were present in 4 cases, 3 with unmutated IgVH and del(17p) and 1 with mutated IgVH and no del(17p). In univariate analysis, the following variables resulted associated to a short TFI: advanced stage Binet B/C and Rai I/IV (<0.0001), WBC count (<0.0001), proportion of CD3+ cells <16% (0.0002), raised beta2-microglobulin (<0.0001) and LDH (<0.0001), unmutated IgVH (<0.0001), CD38+ (<0.0001), ZAP-70+ (<0.0018), adverse cytogenetic abnormalities (del(17p), del(11q), +12) (<0.0001). Atypical CLL morphology showed a trend for significance (0.06). Multivariate analysis on TFI - including WBC count (as continuous variable), CD3 %, LDH, IgVH mutation status, ZAP-70 and CD38 expression and corrected with interaction between WBC and IgVH status - was focused on the 84 patients with Binet stage A. High WBC count, raised LDH, unmutated IgVH resulted as unfavorable prognostic factors, whilst the proportion of CD3+ cells was associated with a better outcome. Neither ZAP-70 or CD38 showed an independent prognostic value. In CLL cases with discordant expression of ZAP-70 and IgVH mutation status (25% of cases), the latter appeared to be more relevant than ZAP-70 in determining the TFI. In conclusion, unmutated IgVH, raised LDH, WBC count and a low proportion of CD3+ cells at diagnosis are significant predictors of TFI in early stage CLL. This group represents about one third of young patients at diagnosis. Adverse FISH abnormalities are present only in a small subgroup of cases in the early phases of the disease. Young CLL patients at diagnosis N° of cases % Raised beta2-microglobulin (>3400 ng/l) 5/102 5% Raised LDH 16/105 15% Hypo IgG 21/98 21% Atypical morphology 27/104 26% CD3+ cells (<16%) 60/105 57% CD4/CD8 (<1) 3/101 3% IgVH mutated (≥98%) 67/103 65% IgVH unmutated (<98%) 36/103 35% CD38 ≥7% 25/104 24% ZAP-70 ≥10% 39/100 39% Del(17p) >20% 2/104 2% Del(11q) >10% 7/104 7% +12 >5% 7/104 7% Del(13q) >5% isolated 59/104 57% Normal (none of the above) 29/104 28% p53 protein expression 3/100 3% p53 gene mutation 4/105 4%

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.

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