Clinical Impact of TP53 Gene Mutations in Diffuse Large B-Cell Lymphoma (DLBCL): An International DLBCL Rituxan-CHOP Consortium Program Study.

Abstract Abstract 967 Mutations of the TP53 tumor suppressor gene are associated with a poor clinical outcome in DLBCL patients treated with CHOP. The impact of TP53 mutations on clinical outcome of DLBCL patients treated with Rituxan-CHOP has not been comprehensively analyzed. The purpose of this study was to analyze the frequency and type of TP53 mutations in Rituxan-CHOP treated DLBCL patients from twenty-two medical centers, and to correlate these with clinical outcome. TP53 mutations were identified in 138/604 (22.7%) Rituxan-CHOP treated DLBCL cases and included missense (n=133), nonsense (n=16), splice site (n=9) and frameshift (n=1) mutations. The presence of any TP53 mutation correlated with poor overall survival (OS) with a median OS of 50 months in the TP53 mutation group versus 69 months in the wild-type group (wt-TP53, P=0.0042). Seventy-three of 138 cases (53%) had mutations in the DNA binding domains of the TP53 gene, which were found to be the most important predictor of poor OS (P=0.0044). In contrast, mutations in the non-DNA binding domains did not correlate with poor OS (P=0.157). Overexpression of p53 protein significantly correlated with only TP53 missense mutations (P=0.002), but not with other types of TP53 mutations, while TP53 deletion did not correlate with mutation or OS. In comparison to our previous series of patients treated only with CHOP, Rituxan-CHOP regimen improved OS in both wt-TP53 and TP53 mutated groups. The 5-year survival rate was 42% in patients with any TP53 mutation (median survival=50 months) and 41% in patients with the DNA-binding domain mutations (median survival=49 months) compared to 52% for those with wt-TP53 (median survival=69 months). The complete remission rate was 51% in patients with any TP53 mutation and 44% in patients with the DNA-binding domain mutations, compared to 77% for those with wt-TP53. However, the clinical outcome and treatment response to the Rituxan-CHOP varied in patients with mutations in different regions of the DNA-binding domains. Patients with mutations in the DNA minor binding groove motif (Loop L3, 17% of all mutations) had significantly decreased median OS (17 months) when compared to patients with Loop L2 (16% of all mutations) or loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) with median OS of 49 and 50 months, respectively. In contrast to our previous CHOP series study, median survival was significantly improved for Rituxan-CHOP treated DLBCL patients with mutations in the loop-sheet-helix motifs (43 months). Multivariate analysis confirmed that TP53 mutations and activated B-cell-like (ABC)/germinal center B-cell-like (GCB) subtype classification were independent predictors of OS with a hazard ratio of 0.69 (GCB vs ABC, 95% CI 0.49-0.98) and 1.60 (TP53 vs wt-TP53, 95% CI 1.10-2.31), respectively. Similar to our previous CHOP study, the TP53 mutation profile, regardless of location, was found to stratify GCB-DLBCL, but not ABC-DLBCL, into molecularly distinct subsets with different clinical outcomes in Rituxan-CHOP treated DLBCL patients. This study demonstrates the importance of TP53 mutational profile for predicting clinical outcome. Elucidation of the roles of specific TP53 domain mutations, as documented in our study, will help in refining prognostic models for DLBCL patients treated with either the CHOP or Rituxan-CHOP regimen. These findings also provide the rationale and strategies for p53 targeted therapeutic intervention in DLBCL patients. Disclosures: Kahl: Milllennium: Consultancy, Research Funding; Cephalon: Consultancy, Research Funding.

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Structural Profiles of p53 Gene Mutations Predict Clinical Outcome in Diffuse Large B-Cell Lymphoma: An International Collaborative Study.

Blood ◽

10.1182/blood.v108.11.811.811 ◽

2006 ◽

Vol 108 (11) ◽

pp. 811-811

Author(s):

Ken H. Young ◽

Karen Leory ◽

Michael B. Møller ◽

Margarita Sánchez-Beato ◽

Gisele W.B. Colleoni ◽

...

Keyword(s):

Dna Binding ◽

Clinical Outcome ◽

B Cell ◽

Median Survival ◽

P53 Gene ◽

B Cell Lymphoma ◽

P53 Mutation ◽

Dna Binding Domains ◽

Binding Domains ◽

Large B Cell Lymphoma

Abstract Mutations of the p53 tumor suppressor gene have been associated with a poor clinical outcome in some series of diffuse large B-cell lymphoma (DLBCL). However, conflicting results have been reported in other studies. The purpose of this study was to analyze the p53 mutations in DLBCL from twelve centers, and to correlate the structural profiles of the mutations with clinical outcome. The p53 mutations were identified in 102 of 477 cases of DLBCL for a frequency of 21.4%. These included 92 missense mutations, 5 nonsense mutations, 4 deletions, and 1 insertion. The presence of any p53 mutation correlated with poor overall survival (OS; P=0.002). Sixty-two of 102 cases (61%) had mutations in the DNA binding domains of the p53 gene, and the mutations in the DNA-binding domains were found to be the most important predictor of poor OS (P<0.001). In contrast, mutations in the non-DNA binding domains did not correlate with OS (P=0.158). The 5-year survival rate was 24% in patients with any p53 mutation (median survival=1.33 yr) and 19% of patients with the DNA-binding domain mutations (median survival=1.0 yr) compared to 41% for those with wild type p53 (wt-p53, median survival=4.5 yr). The complete remission rate was 57% in patients with any p53 mutation and 54% in patients with the DNA-binding domain mutations compared to 69% for those with wt-p53. Of the mutations in the DNA-binding domains, patients with mutations in the loop-sheet-helix motifs (Loop L1-S10-H2, 20% of all mutations) and DNA minor binding groove motif (Loop L3, 22% of all mutations) had significantly decreased OS (P=0.002). In contrast, OS was not significantly decreased for patients with mutations in Loop L2 (18% of all mutations). Multivariate analysis confirmed that the International Prognostic Index, age, tumor size, serum lactate dehydrogenase, and mutations in the DNA binding motifs were independent predictors of OS. The p53 mutation profile was also found to stratify germinal center B-cell-like DLBCL, but not activated B-cell-like DLBCL, into molecularly distinct subsets with different clinical outcomes. This study demonstrates the importance of the mutational profile in the DNA binding domains of the p53 gene for predicting clinical outcome and refining current prognostic models including gene expression profiling in patients with DLBCL.

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Structural profiles of TP53 gene mutations predict clinical outcome in diffuse large B-cell lymphoma: an international collaborative study

Blood ◽

10.1182/blood-2008-01-129783 ◽

2008 ◽

Vol 112 (8) ◽

pp. 3088-3098 ◽

Cited By ~ 103

Author(s):

Ken H. Young ◽

Karen Leroy ◽

Michael B. Møller ◽

Gisele W. B. Colleoni ◽

Margarita Sánchez-Beato ◽

...

Keyword(s):

Dna Binding ◽

B Cell ◽

Cell Lymphoma ◽

Gene Mutations ◽

B Cell Lymphoma ◽

Tp53 Gene ◽

Tp53 Mutations ◽

Dna Binding Domains ◽

Binding Domains ◽

Large B Cell Lymphoma

AbstractThe purpose of this study is to correlate the presence of TP53 gene mutations with the clinical outcome of a cohort of patients with diffuse large B-cell lymphoma (DLBCL) assembled from 12 medical centers. TP53 mutations were identified in 102 of 477 patients, and the overall survival (OS) of patients with TP53 mutations was significantly worse than those with wild-type TP53 (P < .001). However, subsets of TP53 mutations were found to have different effects on OS. Mutations in the TP53 DNA-binding domains were the strongest predictors of poor OS (P < .001). Mutations in the Loop-Sheet-Helix and Loop-L3 were associated with significantly decreased OS (P = .002), but OS was not significantly affected by mutations in Loop-L2. A subset of missense mutations (His158, His175, Ser245, Gln248, His273, Arg280, and Arg282) in the DNA-binding domains had the worst prognosis. Multivariate analysis confirmed that the International Prognostic Index and mutations in the DNA-binding domains were independent predictors of OS. TP53 mutations also stratified patients with germinal center B cell–like DLBCL, but not nongerminal center B cell–like DLBCL, into molecularly distinct subsets with different survivals. This study shows the prognostic importance of mutations in the TP53 DNA-binding domains in patients with DLBCL.

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BSAP Can Repress Enhancer Activity by Targeting PU.1 Function

Molecular and Cellular Biology ◽

10.1128/mcb.20.6.1911-1922.2000 ◽

2000 ◽

Vol 20 (6) ◽

pp. 1911-1922 ◽

Cited By ~ 53

Author(s):

Shanak Maitra ◽

Michael Atchison

Keyword(s):

Transcription Factors ◽

Cell Differentiation ◽

Dna Binding ◽

B Cell ◽

Transactivation Domain ◽

B Cell Differentiation ◽

Developmentally Regulated ◽

Enhancer Activity ◽

Dna Binding Domains ◽

Binding Domains

ABSTRACT PU.1 and BSAP are transcription factors crucial for proper B-cell development. Absence of PU.1 results in loss of B, T, and myeloid cells, while absence of BSAP results in an early block in B-cell differentiation. Both of these proteins bind to the immunoglobulin κ chain 3′ enhancer, which is developmentally regulated during B-cell differentiation. We find here that BSAP can repress 3′ enhancer activity. This repression can occur in plasmacytoma lines or in a non-B-cell line in which the enhancer is activated by addition of the appropriate enhancer binding transcription factors. We show that the transcription factor PU.1 is a target of the BSAP-mediated repression. Although PU.1 and BSAP can physically interact through their respective DNA binding domains, this interaction does not affect DNA binding. When PU.1 function is assayed in isolation on a multimerized PU.1 binding site, BSAP targets a portion of the PU.1 transactivation domain (residues 7 to 30) for repression. The BSAP inhibitory domain (residues 358 to 385) is needed for this repression. Interestingly, the coactivator protein p300 can eliminate this BSAP-mediated repression. We also show that PU.1 can inhibit BSAP transactivation and that this repression requires PU.1 amino acids 7 to 30. Transfection of p300 resulted in only a partial reversal of PU.1-mediated repression of BSAP. When PU.1 function is assayed in the context of the immunoglobulin κ chain 3′ enhancer and associated binding proteins, BSAP represses PU.1 function by a distinct mechanism. This repression does not require the PU.1 transactivation or PEST domains and cannot be reversed by p300 expression. The possible roles of BSAP and PU.1 antagonistic activities in hematopoietic development are discussed.

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Next Generation Sequencing (NGS) of TP53 Gene Allows to Identify a Very High Risk Group of Philadelphia Negative Acute Lymphoblastic Leukemia (ALL) Patients

Blood ◽

10.1182/blood.v124.21.3796.3796 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3796-3796

Author(s):

Silvia Salmoiraghi ◽

Greta Ubiali ◽

Manuela Tosi ◽

Barbara Peruta ◽

Marie Lorena Guinea Montalvo ◽

...

Keyword(s):

Clinical Outcome ◽

Tp53 Mutation ◽

Lymphoblastic Leukemia ◽

Tp53 Gene ◽

Wild Type ◽

Poor Clinical Outcome ◽

Tp53 Mutations ◽

Next Generation Sequencing Ngs ◽

Roche Diagnostics ◽

Generation Sequencing

Abstract Background and Aim of the Study For both childhood and adult Acute Lymphoblastic Leukemia (ALL) patients, clinical risk factors such as age, white cell count, response to steroids, time to complete remission, as well as biologic characteristics such as immunophenotype and cytogenetic at diagnosis are important but not sufficient in predicting clinical outcome. Aberrations of TP53 play a crucial role in the molecular pathogenesis of leukemias and lymphomas in which their presence is associated to disease progression and represents a strong predictor of poor clinical outcome. In childhood ALL, hereditary and acquired TP53 mutations are involved both in the pathogenesis and progression of the disease. In adult ALL, TP53 mutations are frequent in patients negative for recurrent fusion genes and correlate with poor response to induction therapy (Chiaretti S. et al, Haematologica 2013). The aim of this study was to evaluate the impact of TP53 alterations, analyzed by Next Generation Sequencing (NGS), on the outcome of a cohort of T (n= 57) and B (n= 114) precursor, Philadelphia (Ph) negative, adult ALL patients enrolled into the NILG-ALL 09/2000 clinical trial (ClinicalTrials.gov identifier: NCT00358072, Bassan R. et al, Blood 2009) in which molecular minimal residual disease was used to guide post-remissional therapy. Patients and Study design Among the 171 patients who were investigated for TP53 mutations, 16 proved also positive for t(4;11) and 3 for t(1;19). We analyzed DNA isolated from mononuclear cells obtained from bone marrow or peripheral blood samples containing at least 30% of blasts at diagnosis. The TP53 gene was sequenced using 454 ultra-deep sequencing (Roche Diagnostics) for alterations in exons 4 to 11, following the protocol developed in the IRON-II consortium. The sequencing data were analyzed by the Roche Diagnostics GS Run Browser and GS Amplicon Variant Analyzer software. The probabilities of survival were estimated using the Kaplan Meier method. The log-rank test was used to compare survival probabilities between subgroups of patients. Results and Discussion The data obtained by NGS allowed to identify 15 coding mutations detected in the DNA binding domain region (exons 5 to 8). These alterations were observed at diagnosis in 14 patients (8%), (11 B-precursor ALL and 3 T-ALL). In 12 cases these aberrations were single nucleotide changes, in 2 cases we found a duplication (one of 4 and the other of 8 nucleotides) and in one case there was an 11 base pair DNA insertion. Remarkably, all of these DNA alterations led to missense or frame-shift mutations that introduced a premature stop codon. Moreover, they were detected with a wide range of allele burden (from 5% to 97%) pointing out that TP53 mutations can be present at diagnosis in different proportions within the leukemic clones. All patients carrying a TP53 alteration reached complete remission after induction therapy but 13 out of 14 suffered an early relapse. Frequency of relapses was significantly higher in mutated than in wild-type cases (p=0.019). Relapse DNA samples were available in 3 patients and in all of them we detected the same TP53 mutation found at diagnosis, indicating the presence of a stable mutated clone. The univariate analysis enlightens a clear relationship between TP53 mutation with an increasing age (p= 0.0003) but no correlation with other clinical features such as gender, hemoglobin, white blood count, platelets, percentage of blasts and cytogenetics at diagnosis. Moreover, patients with mutated TP53 showed a Disease Free Survival (DFS) and Overall Survival (OS) dramatically shorter than wild-type patients. The 2 years DFS was 43% in the TP53 non-mutated subjects compared to 7% in the mutated (p=0.0007). Similarly, the 2 years OS was of 50% in wild-type patients and of 7% in mutated patients (p=0.0011) (Figure 1). Conclusions In adult ALL, response to induction chemotherapy is not different in patients with a wild-type or a TP53 mutated gene, but in these latter cases the leukemia relapse rate is dramatically higher. The frequency of these mutations observed at diagnosis and the poor clinical outcome indicate the need of their identification during the diagnostic work up of adult ALL to guide treatment strategies. The use of a highly sensitive deep sequencing approach is crucial to identify also minor leukemic clones carrying TP53 mutations that may lead to the rapid emergence of a treatment resistant disease. Disclosures Kohlmann: AstraZeneca: Employment.

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B-Cell Coactivator OBF-1 Exhibits Unusual Transcriptional Properties and Functions in a DNA-Bound Oct-1-Dependent Fashion

Molecular and Cellular Biology ◽

10.1128/mcb.19.6.4247 ◽

1999 ◽

Vol 19 (6) ◽

pp. 4247-4254 ◽

Cited By ~ 8

Author(s):

Andrea Krapp ◽

Michel Strubin

Keyword(s):

Dna Binding ◽

B Cell ◽

Target Genes ◽

Regulatory Elements ◽

Binding Domain ◽

Dna Binding Domain ◽

Activation Domain ◽

Activation Domains ◽

Dna Binding Domains ◽

Binding Domains

ABSTRACT Eukaryotic transcriptional activators generally comprise both a DNA-binding domain that recognizes specific cis-regulatory elements in the target genes and an activation domain which is essential for transcriptional stimulation. Activation domains typically behave as structurally and functionally autonomous modules that retain their intrinsic activities when directed to a promoter by a variety of heterologous DNA-binding domains. Here we report that OBF-1, a B-cell-specific coactivator for transcription factor Oct-1, challenges this traditional view in that it contains an atypical activation domain that exhibits two unexpected functional properties when tested in the yeast Saccharomyces cerevisiae. First, OBF-1 by itself has essentially no intrinsic activation potential, yet it strongly synergizes with other activation domains such as VP16 and Gal4. Second, OBF-1 exerts its effect in association with DNA-bound Oct-1 but is inactive when attached to a heterologous DNA-binding domain. These findings suggest that activation by OBF-1 is not obtained by simple recruitment of the coactivator to the promoter but requires interaction with DNA-bound Oct-1 to stimulate a step distinct from those regulated by classical activation domains.

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Mutations in TP53 Gene Is Independent Prognostic Factor for High Grade B-Cell Lymphoma

Blood ◽

10.1182/blood.v128.22.5402.5402 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5402-5402

Author(s):

Anna Evgenevna Misyurina ◽

Vsevolod Andreevich Misyurin ◽

Andrey Vitalievich Misyurin ◽

Alla Mikhailovna Kovrigina ◽

Sergey Kirillovich Kravchenko ◽

...

Keyword(s):

Adverse Effect ◽

Prognostic Factor ◽

B Cell ◽

Tp53 Mutation ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Tp53 Gene ◽

Independent Prognostic Factor ◽

High Grade ◽

Tp53 Mutations

Abstract Background. TP53 mutations were described to have a negative impact on prognosis of patients with B-chronic lymphoid leukemia and diffuse large cell lymphoma. However, a role of TP53 mutations in high-grade B-cell lymphomas (HGL) is not well defined in context of other genetic aberrations. Materials and methods. 23 patients (7 males and 16 females) had diagnosis of HGL were treated in National Research Center for hematology, Moscow, Russia. Median age was 49 years old (30-76). 5 patients had HGL with c-MYC (MYC-R) and BCL2 genes rearrangements and 2 - HGB with MYC-R and BCL6 rearrangements. 17 (74%) patients had MYC-R, 11/23 (48%) had double expresser lymphoma (MYC≥40%, BCL2≥50%) (DE). Median of observation time was 29,1 months (6,3-99,8). 19 (82%) of patients had IPI score 3-5 points. 16 patients underwent LM-B-04 with rituximab (Table 1), 5 - R-(DA)-EPOCH, 2 - R-CHOP-21. In 5 cases autologous stem cell transplantation was performed. Sanger sequencing was performed to identify mutations in exons 5-8 of TP53 gene using DNA extracted from formalin fixed paraffin embedded tissue («Extra-DNA» kit, «Genetechnology» LLC). Primers to TP53 gene were synthesized based on nucleotide sequences data available online on website ncbi.com by «Evrogene». To evaluate an influence of such factors as TP53 mutation (TP53mut), MYC-R, DHL, DE, gender, therapy on overall survival (OS) and time to progression (TTP) were performed multivariate dispersion analysis and Cox regression analysis (STATISTICA 10). Results: 8 (35%) cases with TP53mut were identified: c.535C>T 45,6% p.H179Y, c.524G>C 15,6% p.R175P, c.743G>A 75,6% p.R247Q, c.487T>A 25,2% p.Y163N, c.824G>A 75% p.C275Y, c.713G>A 87,7% p.C238Y, c.745A>G 31,9% p.R249G, c.639A>G 41,8% p.R213R. 7/8 of them harbored MYC-R, 2/8 had DHL. In univariate (Picture 1, 2) and multivariate analysis pts harboring TP53mut had worse OS (median OS was 6,2 (0,7-9,5) vs 25,5 (0,7-99,8) months, p=0,004) and shorter TTP (median TTP 3,5 (0,7-9,5) vs 23,1 (0,7-99,8) months, p=0,027) than patients without TP53mut. DHL status had also an adverse effect on OS with lower significance than in pts with TP53mut (p=0,022). Adverse effect of TP53mut trends to play a role in combination with c-MYC gene rearrangement, thus5 pts TP53mut/MYC-R had shorter TTP than 5 DHL pts (3,4 (1,1-9,5) vs 7,3 (0,6-67,1) months, p=0,07). Conclusion: High-grade lymphoma has a more powerful and independent prognostic factor than double-hit status - TP53 mutation that contribute inferior prognosis. This factor shouldn't be underestimated in routine diagnostics because of its frequency and requirement of a different therapeutic approach. Disclosures No relevant conflicts of interest to declare.

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Comparison the Distinct Clinical Outcome with TP53 Mutation Status in MDS and AML :an Retrospective Study

Blood ◽

10.1182/blood-2019-124622 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5405-5405

Author(s):

Xinrong Xiang ◽

Yang Ou ◽

Yu Wu

Keyword(s):

Overall Survival ◽

Dna Binding ◽

Clinical Outcome ◽

Tp53 Mutation ◽

Binding Domain ◽

Dna Binding Domain ◽

Missense Mutations ◽

Hypomethylating Agents ◽

Tp53 Mutations

Background: The TP5 gene is by far the most frequently mutated gene in human cancer. Some studies have shown that TP53 should be used as an independent prognostic biomarker in the prognostic stratification of myelodysplastic syndromes(MDS) and acute myeloid leukemia (AML). In this study, we want to explore the effects of different TP53 mutation status on clinical outcomes in AML and MDS. Method and Results: We retrospectively collected and analyzed 51 patients with TP53 mutation from Jan 1st , 2015 to May 1st , 2019 in West China Hospital, Sichuan University, China. Among 51 patients, 27 patients were diagnosed as MDS,11 were diagnosed as AML. Then average age is 55.7(15-77). According to IPSS-R of MDS, there are 18 out of 27 patients in the high-risk and very high-risk groups, only 1 patient in the intermediate risk group and 8 patients lost follow up. 10 out of 11 AML patients were in the high risk group according to the NCCN guideline. In our analysis, the incidences of complex karyotype and additional gene mutations were 86.67% and 36.84% in MDS and AML patients. AML evolution was 40.74% in MDS patients. The median follow-up time was 16 months (4-51 months) and the median overall survival was 7.61 months (range, 2-17 months). So far, 28.95% patients are still being treated, of which 9 have been treated with hypomethylating agents. To compare the clinical outcome with different TP53 mutations status, firstly, we identified the mutation types and various mutants activity. We counted 62 TP53 mutations in 51 patients and marked their sites at the transcriptional level in Fig1 . Codons 248, 273, 175, 282, 245, and 249 are most common somatic mutations in TP53. Herein, the TP53 mutation hot spots found in 38 AML or MDS patients are clustered in the DNA-binding domain. Then we used the luciferase reporting system to test the p53 mutant activity with missense mutations in the DNA-binding domain as a transcription factor. The results in Fig2 showed that with the exception of R158H, M237V , V143M , Q136E and H178Q, almost all the other mutation types have no activity. And we demonstrated these TP53 hotspot mutations in the structure ( Figure 3). The overall survival time of patients with residual P53 mutant activity (except for the compound mutation) far exceeded the median overall survival(7.61months). For the other patients with mutants which almost completely lost the activity of p53 protein as a transcription factor, two patients were treated with hypomethylating agents followed by hematopoietic stem cell transplantation have survived for 14 and 11 months after diagnosis, respectively. As shown in Fig4 and Fig 5, we compared the OS of these two group patients with different P53 mutant activity and different function areas for 6 months and 12 months, respectively. The results showed that the patients with residual P53 activity survived better Conclusion: Patients with different TP53 mutations do have different clinical outcomes. Patients with residual P53 mutant activity do respond better to treatment, and the final clinical outcome of patients who lose P53 activity completely is poor, but hypomethylating agents and hematopoietic stem cell transplantation can also ppropriately prolong survival time. Legends to the figures Figure1: 62 TP53 mutations in 51 patients with hematological neoplasms. The TP53 mutation hot spots found in 38 AML or MDS patients are clustered in the DNA-binding domain. There were 9 patients with multiple TP53 mutations. The black label represents somatic mutation, and the red label represents germline mutation. Missense mutations account for 61.70%(29/47) of all the TP53 mutations in 38 patients. Figure 2: The p53 mutant activity with missense mutations in DNA binding domain tested by the luciferase reporting system. We compared the normalized RLU on PUMA of P53 mutant with wild type. Figure 3: The structure of the p53 core domain bound to DNA. We marked the residues affected by the TP53 hotspot mutations . The deeper the red, the higher the mutation frequency and the more the mutation clustered Figure 4 : The overall survival of 30 follow-up patients. We use a bar chart to show the clinical outcome(OS) of 30 patients with different mutation types and P53 structure affected by different p53 domains. Figure 5 : The probability of overall survival of 30 follow-up patients. They are divided in two groups: patients with residual P53 activity VS patients with inactive P53 mutant. Disclosures No relevant conflicts of interest to declare.

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