The vast majority of de novo acute myeloid leukemia (AML) present unaltered TP53 alleles. Evolutionary Action score (EAp53) is a computationally derived score to quan- TP53 disruption in chronic lymphocytic leukaemia (CLL) is a well-established prognostic marker and informs on the appropriate course of treatment for patients. Genomic aberrations and survival in chronic lymphocytic leukemia. Piek JM, van Diest PJ, Zweemer RP, Jansen JW, Poort-Keesom RJ, Menko FH, et al. Pharmacologic strategies able to stabilize both WT and mutant TP53 promoting the reactivation of tumor-suppressor activities are under study in AML. reported that the cytotoxic effects of standard chemotherapies do not directly produce TP53 mutations. Metabolic functions of the tumor suppressor p53: Implications in normal physiology, metabolic disorders, and cancer. The TP53 protein is … Oncotarget (2017) 8:32550–65. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Nat Rev Mol Cell Biol (2014) 15(7):433–52. Somatic mutations predict outcomes of hypomethylating therapy in patients with myelodysplastic syndrome. P53 reactivation with induction of massive apoptosis-1 (PRIMA-1) inhibits amyloid aggregation of mutant p53 in cancer cells. 126. This suggests a possible resistance mechanism to HMA therapy and provides rationale for combination therapy. Signal integration by JNK and p38 MAPK pathways in cancer development. TP53 is a key tumor suppressor gene with protean functions associated with preservation of genomic balance, including regulation of cellular senescence, apoptotic pathways, metabolism functions, and DNA repair. Dohner H, Dolnik A, Tang L, Seymour JF, Minden MD, Stone RM, et al. Patients and Methods We assessed TP53 mutations by denaturing high-performance liquid chromatography (exons 2 to 11) in a randomized prospective trial (n = 375) with a … The combination of VEN/HMAs seems also to give some benefit in this setting, improving response rates and remission duration and potentially representing a safe bridge to transplantation for selected more patients. 54. In fact, all patients with TP53 deletion showed significantly poorer 2-year DFS as well as shorter 2-year OS compared to patients with complex aberrancy without TP53 deletion (29). This article collection reviews the medical genetics of acute myeloid leukemia and includes 30 papers by various authors. In addition, MRD negativity was observed in 57% of responders and median duration or median survival was not reached with a median follow-up of 6.9 months. Cancer Discovery (2018) 9(3):370–83. Chang CK, Zhao YS, Xu F. TP53 mutations predict decitabine-induced complete responses in patients with myelodysplastic syndromes. doi: 10.1007/s00018-017-2575-0, 16. Blood (2018) 132(Supplement 1):3091. doi: 10.1182/blood-2018-99-119990, 119. TP53 multi-hit state resulted in combination with high-risk occurrence, complex karyotype, and dismal survival and predicted risk of leukemic transformation and death regardless of the Revised International Prognostic Scoring System, while patients presenting mono-allelic alterations did not show differences when compared with those with WT-TP53 (43). However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. 51. 11 In addition, the clinical relevance of the number of cells displaying … J Biol Chem (2011) 286:17478– 17486. doi: 10.1074/jbc.M111.231639, 144. JCO 2001; Devillier R et al. Unconventional strategies and TP53-targeted therapeutics are now being tested as monotherapy or in combination with conventional drugs in order to further improve the response rate especially in R/R AML patients and to increase the number of patients potentially eligible for transplantation, which remains the only curative option for these patients. Nat Cell Biol (2016) 18:1233–43. TP53 is often also called by its older name “p53.”. They observed that the median leukemia free survival was significantly shorter in the subset of patients with p53 overexpression (9 vs 55 months; p = 0.026), including those who were consolidated with allogeneic stem-cell transplantation (ASCT) (32). TP53 aberrations are defined as 17p deletions by hierarchical FISH or TP53 mutations by sequencing plus FISH. -. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Mutations in transcription factor TP53 is important in cell cycle arrest for DNA mismatch repair, base excision repair, and nucleotide excision repair. Leukemia (2008) 22:1539–41. Genes Dev (1993) 7:1126–32. Mutations of epigenetic regulators and of the spliceosome machinery in therapy-related myeloid neoplasms and in acute leukemias evolved from chronic myeloproliferative diseases. TP53 alteration in chronic lymphocytic leukemia indicates a high-risk disease that is usually refractory to chemotherapy. TP53 mutations are significantly associated with complex or monosomal karyotypes (p<0.001, see Table 1). Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) who have unfavorable-risk cytogenetic abnormalities and TP53 mutations responded to treatment with decitabine, according to research published in the New England Journal of Medicine.However, patients who responded to decitabine treatment never experienced complete mutation clearance. Specific molecular targets include G2/M regulators (CHK1/2, MK2, PLK2) (109–111) kinases (SGK2, MPS1) (112, 113) and growth pathways (p38, DAPK1) (114, 115). Found insideThis is the first in-depth review of the epidemiology of the various leukemias by cell types. N Engl J Med (2016) 375(2):143–53. Cancer (2016) 122(22):3484–91. Conversely to the vast majority of tumor suppressor genes that are predominantly characterized by truncating mutations, a substantial proportion of TP53 alterations include missense substitutions (75%); other mutations are frameshift insertions and deletions (9%), non-sense mutations (7%), silent mutations (5%), and other rare aberrations (2%). Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. 53. Aldoss I, Zhang J, Pillai R, Shouse G, Sanchez JF, Mei M, et al. Rangel LP, Ferretti GDS, Costa CL, Andrade S, Carvalho RS, Costa D. Silva JL. TP53 mutation analysis by Sanger sequencing. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations. 2016 Dec 6;7(49):80916-80924. doi: 10.18632/oncotarget.13106. The vast majority of de novo acute myeloid leukemia (AML) present unaltered TP53 alleles. Blood (2014) 124:2162. doi: 10.1182/blood.V124.21.2162.2162, 141. Genes Cancer (2011) 2:466–74. It has been reported that ATO is able to inactivate TP53 functions via the 26S proteasome pathway (142). San Diego, CA. Contrariwise, in high-grade serous ovarian tumors, TP53 mutations are a relatively precocious event, likely arising in forerunner lesions (9, 10). Muller PA, Vousden KH. Garces S, Khoury JD, Kanagal-Shamanna R, Salem A, Wang SA, Ok CY, Hu S, Patel KP, Routbort MJ, Luthra R, Tang G, Schlette EJ, Bueso-Ramos CE, Medeiros LJ, Loghavi S. Hum Pathol. An MD Anderson Cancer Center (MDACC) study, which collected 108 consecutive patients with t-MDS/t-AML showed that TP53 mutations in this setting were predominantly located in DNA-binding domains presenting an allelic frequency of 37% (range between 7.1 and 98.8). TP53 mutation and survival in chronic lymphocytic leukemia. Several studies show that somatic mutations in the TP53 gene are present in up to 50% of patients with relapsed or refractory chronic lymphocytic leukemia. Anensen N, Hjelle SM, Van Belle W, Haaland I, Silden E, Bourdon JC, et al. MAPKAP kinase-2 is a cell cycle checkpoint kinase that regulates the G2/M transition and S phase progression in response to UV irradiation. J Clin Oncol (2010) 28(29):4473–9. analyzed survival outcomes according to p53 expression level quantified in bone marrow core biopsy samples using immunohistochemistry and computer‐assisted image analysis, in patients with diploid karyotype. For instance, IDH1/2 gene acquires a novel function to convert α-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG) determining the inhibition of TET2 as well as some histone demethylase and promoting tumorigenesis (3). Santos FP, Faderl S, Garcia-Manero G, Koller C, Beran M, O’Brien S, et al. demonstrated in univariate and multivariate analyses that TP53 mutations were the unique molecular abnormalities, which predicted a CR achievement after DAC in patients with MDS (78). The combination fueled a 10-fold increase in ALL mutations, including an alteration in the tumour suppressor gene TP53. Pedersen-Bjergaard J.Mutations of the PTPN11 gene in therapy-related MDS and AML with rare balanced chromosome translocations. TP53 is the sole mutated gene detected in up to 75% of patients, while patients who harbor co-occurring mutations show a lower incidence of mutations in several AML-related genes such as NPM1, FLT3, IDH1, IDH2, WT1, DNMT3A, RUNX1, and RAS (20, 21). A) Map of TP53 mutations in patients treated with CPX-351. Search for other works by this author on: © 2018 by The American Society of Hematology, Copyright ©2020 by American Society of Hematology, 615. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. Cancer risks. Primary and adaptive resistance to VEN-based combinations were mainly correlated with two major mechanisms of resistance: activated kinase signaling and bi-allelic TP53 perturbation. Their book also covers the management of acute leukemia in general as well as the development of new therapies. This book will be extremely useful to clinicians. Kotler E, Shani O, Goldfeld G, Lotan-Pompan M, Tarcic O, Gershoni A, et al. A tumor suppressor gene works like the brakes on a car. Clinical implications of subclonal TP53 mutations in acute myeloid leukemia. Unravelling mechanisms of p53-mediated tumour suppression. Nature (2000) 408:307–10. Double immune checkpoint inhibitor blockade with nivolumab and ipilimumab with or without azacitidine in patients with myelodysplastic syndrome (MDS). The text is balanced with large numbers of full color images, graphs, charts, and tables to assist the reader in understanding these highly technical issues. * Emphasizes the immunophenotypic features, cytogenetic studies, and diagnostic ... doi: 10.3390/ijms21103432, Keywords: acute myeloid leukemia, TP53 mutations, poor outcome, decitabine, venetoclax (BCL-2 inhibitor), Citation: Molica M, Mazzone C, Niscola P and de Fabritiis P (2021) TP53 Mutations in Acute Myeloid Leukemia: Still a Daunting Challenge? Nat Rev Canc (2004) 4(10):793–805. 127. Ross L, Peter JM. Zenz T, Häbe S, Denzel T, Mohr J, Winkler D, Bühler A, Sarno A, Groner S, Mertens D, Busch R, Hallek M, Döhner H, Stilgenbauer S. Blood. 2018;131:1820–32. doi: 10.1056/NEJMoa1301689, 25. P53 gene mutations in acute myeloid leukemia with 17p monosomy. Centrosomes and checkpoints: the MPS1 family of kinases. Missense mutations appeared the most commonly detected, followed by non-sense and frameshift alterations and the TP53 mutation pattern was notably similar to that observed in newly diagnosed MDS/AML (29). doi: 10.1158/1078-0432.CCR-14-2506, 140. Kitamura T, Watanabe-Okochi N, Enomoto Y, Nakahara F, Oki T, Komeno Y, et al. TP53 gene mutation are present in < 10% of patients with de novo AML, 20–37% of patients with sAML/tAML, and up to 70% of patients with a complex karyotype. The overall response rate (ORR) was 47 and 24% in de novo and R/R patients with AML, respectively; all six patients with negative MRD obtained a complete cytogenetic response after receiving VEN and maintained a CR for a median of 3.4 months (97) (Table 3). Analysis of the respective frequency of TP53 mutations across the TCGA datasets shows that AML is one of the tumors with the lowest TP53 alteration rate among all human cancers (24). Overall, the median follow-up was 49 months. “TP53 aberrations have been the strongest negative predictor of survival in CLL. The prognostic impact of 17p (p53) deletion in 2272 adults with acute myeloid leukemia. The authors investigated the outcomes of patients with TP53 mut AML who were treated with a 10-day decitabine … In: American society of hematology annual meeting. Cancer Cell (2014) 25:304–17. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Ipilimumab for patients with relapse after allogeneic transplantation. Oncotarget (2014) 5:8924–36. Found insideOver the past 3 decades, the regulation of p53 has been extensively studied. However, the regulation of mutant p53 remained largely unexplored. This snapshot focuses on recent discovery of mutant p53 GOF and regulation. Bi-directional sequencing of TP53 exons 4-9. Leukemia (2012) 26:1106–7. Found insideThis book, written by world-leading p53 researchers including many of those who have shaped the field over the past 25 years, provides unique insights into the progress of the field and the prospects for better cancer diagnosis and therapy ... doi: 10.1056/NEJMoa1516192, 14. Furthermore, in this cohort, response rates were similar comparing patients who received either a 5‐ or a 10‐day schedule of DAC plus VEN and the VAF of TP53-mutated cases was comparable in responders and non‐responders, conversely to an MDS trial in which TP53 VAF affected outcomes of patients treated with HMAs (96). TP53 mutation. These data suggest that specific recommendations could be considered in patients with AML expressing p53 protein stabilization and to those exhibiting Mdm2 protein overexpression. Found insideThis book provides an unprecedented overview of "Targeted Therapies" for acute myeloid leukemias. Here are examples of genes that can play a role in hereditary cancer syndromes. The most commonly mutated gene in all cancers is TP53 , which produces a protein that suppresses the growth of tumors . In addition, germline mutations in this gene can cause Li-Fraumeni syndrome , a rare, inherited disorder that leads to a higher risk of developing certain cancers. Efficacy of the combination of venetoclax and hypomethylating agents in relapsed/refractory acute myeloid leukemia. |, Treatment Options Beyond Standard Chemotherapy, Creative Commons Attribution License (CC BY). Mol Cell (2005) 17(1):37–48. doi: 10.1038/nrc1455, 15. First, they did not observe a correlation between baseline TP53 VAF and response. Chronic lymphocytic leukemia with proliferation centers in bone marrow is associated with younger age at initial presentation, complex karyotype, and TP53 disruption. Several approaches, including inactivation of mutant p53, degradation of mutant p53, and restoration of the wild type function of p53, have been studied. doi: 10.1038/387296a0, 28. Sallman DA, Komrokji R, Vaupel C, Cluzeau T, Geyer SM, McGraw KL, et al. A novel hierarchical prognostic model of AML solely based on molecular mutations. In a recent in vitro study, leukemic blast cells deriving from patients with AML and APL were tested with graded doses of ascorbate (ASC), alone or in combination with standard concentration (1 μM) of ATO. In contrast, TP53 mutations unrelated to cytogenetic alterations represent a rare event (28). doi: 10.1101/gad.7.7a.1126, 133. ACS Med Chem Lett (2013) 4:466–9. In the AMLSG cohort a statistically significant superior OS (median 12.9 versus 5.5 months, p = 0.017) and a trend in longer EFS (7.3 vs 5.2 months, p = 0.054) were found for patients with a low-risk RFS comparing with those with a high-risk RFS (69). A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1. Nahi H, Selivanova G, Lehmann S, et al. 2019 Dec;18(24):3442-3455. doi: 10.1080/15384101.2019.1688951. Outcome results of patients presenting high-risk cytogenetic score at diagnosis showed that the presence of TP53 mutations contributed to an inferior rate of complete response (CR) (28% mutated versus 50% un-mutated), and a lower DFS and OS (59). doi: 10.1182/blood-2016-01-693879, 94. Lehmann S, Bykov VJN, Ali D, Andrén O, Cherif H, Tidefelt U, et al. Although all classes of TP53 variants have been observed in AML, the vast majority of mutations include missense alterations usually arising in the DNA binding domain (encoded by exons 5–8) with a predilection for arginine residues and noted mutational “hot spots” such as R175H, Y220C, R248Q, and R273C (13). San Diego, CA. Acute myeloid leukemia: the good, the bad, and the ugly. DiNardo CD, Patel KP, Garcia-Manero G, Luthra R, Pierce S, Borthakur G, et al. Int J Mol Sci (2020) 21(10):3432. Marginal Zone Lymphoma +. Wong E, Dawson E, Davis J, Koldej R, Ludford-Menting M, Lansdown M, et al. Lindsley RC, Brenton GM, Mazzola E, Grauman PV, Shareef S, Allen SL, et al. Decitabine in the treatment of acute myeloid leukemia in elderly patients. Phase 1b results of idasanutlin + cytarabine (ARA-C) in acute myeloid leukemia patients. In addition to trisomy of chromosome 8, others CNAs related to other chromosomes are significantly associated with TP53 mutations: loss of chromosome 5q, deletion of chromosome 3(p22.3), deletion of chromosome 12(p12.3), and gain of chromosome 17(p11.2), chromosome 16p(11.2-11.3), and chromosome 14(q32.33) (42). AB - Acute myeloid leukemia (AML) with intrachromosomal amplification of chromosome 21 (iAMP21) is rare and has not been well characterized. Br J Haematol. Methods: This is a retrospective, multi-center review of patients who received at least 1 cycle of induction chemotherapy with CPX-351 at Memorial Sloan Kettering Cancer Center (MSKCC), Moffitt Cancer Center (MCC), and Weill Cornell Medical College (WCMC). Welch JS. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Ki-67, p53 and BCL-2 Expressions and their Association with Clinical Histopathology of Breast Cancer among Women in Tanzania. N Engl J Med (2013) 368:2059–74. TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. Prokocimer M, Molchadsky A, Rotter V. Perspective dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy. New Engl J Med (2020) 383(7):617–29. Significance and Incidence of TP53 Mutations in de Novo Acute Myeloid Leukemia Oncogene (2012) 31:1533–45. Science (2019) 365:599–604. Using routine immunohistochemistry (IHC), Ruzinova et al. Leuk Res (2015) 39:348–54. Purpose of review Tumor protein 53 (TP53) protein is involved in fundamental processes of cancer, aging, and DNA repair. In summary, chronic lymphocytic leukemia patients with TP53 alterations frequently show atypical morphologic features. A TP53 genetic test looks for a change, known as a mutation, in a gene called TP53 (tumor protein 53). Found inside – Page 36University of Ulm: TP53 mutation profile in chronic lymphocytic leukemia - evidence for a disease specific profile from a comprehensive analysis of 268 ... Background: TP53 is a highly conserved tumor suppressor gene present on chromosome 17 and comprised 11 exons and 12 introns. Mutated TP53. 2021 Jul 6;13(14):3391. doi: 10.3390/cancers13143391. Interestingly in 11 evaluable patients, the combination of these agents provided an ORR of 100% and a CR rate of 82%. A recent phase 2 study of nivolumab in combination with 5-AZA in R/R AML showed tolerable toxicity and an ORR of 33%, although higher response rates were observed in HMAs-naïve patients and those with increased bone marrow and peripheral blood T-cells by flow cytometry (122). The well-known molecular risk factors FLT3-ITD (internal tandem duplication) and NPM1 mutation showed a lower incidence then TP53 deletion in patients with complex karyotype (P < 0.001) (17). To date, AML with TP53 mutations lacks a clinically standardized therapeutic strategy aimed at targeting these alterations. doi: 10.1038/s41375-018-0035-y. These alterations either directly produce the degradation of the DNA-binding domain of TP53 or induce conformational variations of the TP53 protein, thus determining a sever impairment of TP53 functions (27). Found insideEssential medical facts on over 2,000 genetic syndromes. Organized alphabetically, this book provides comprehensive medical coverage for each syndrome, from genetic basis to manifestations to related medical considerations. In a recently published analysis of the European Society for Blood and Marrow Transplantation (EBMT), authors reported that patients with a 17p abnormality who achieved a CR1 and underwent ASCT had a 2-year OS and leukemia-free survival rate of 28 and 24%, respectively. Venetoclax and ypomethylating agents in TP53-muatated acute myeloid leukaemia. Bowen D, Groves MJ, Burnett AK, Patel Y, Allen C, Green E, et al. J Hematol Oncol (2017) 10(1):20. doi: 10.1186/s13045-017-0393-3, 64. MM, CM, and PN wrote the manuscript. Therefore, despite the current fervor for DAC, DAC as monotherapy does not seem to produce deep and durable responses in a TP53-mutated setting, and additional consolidation therapies appear to be necessary. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. These data suggest that sub-clonal TP53 mutations represent a novel significant prognostic factor in AML and may have implications for incorporating NGS among TP53 routinely screening methods and for re-defining future risk stratification in AML. Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. doi: 10.1038/35042675, PubMed Abstract | CrossRef Full Text | Google Scholar, 2. Chronic lymphocytic leukemia is the most common hematologic malignancy among adults in Western countries. Analysis of additional co-mutations and responses will be presented by our collaborators (Talati et al., ASH 2018 submitted). Functional Classification of TP53 Mutations in Acute Myeloid Leukemia. This may mean that both TP53 inactivation is not necessary for the occurrence or maintenance of AML and AML may influence TP53 activities due to alternate mechanisms. Wu X, Bayle JH, Olson D, Levine AJ. TP53 mutation (TP53 mut) confers an adverse prognosis in acute myeloid leukemia (AML).Venetoclax with hypomethylating agents is a current standard for older patients; however, recent reports suggest that TP53 mut confers resistance to venetoclax. The noted correlation between TP53 and high-risk presentation, complex karyotype, rapid leukemic transformation, and poor survival were directly associated with patients displaying the multi-hit state only. Two patterns of TP53 co-mutations often emerged. However, recently Wong et al. CD47 has a key role in signaling pathways and appears overexpressed in myeloid malignancies leading to tumor evasion of phagocytosis by macrophages. Boettcher S, Miller PG, Sharma R, McConkey M, Leventhal M, Krivtsov AV, et al. Oncol. Clinical implications of cancer gene mutations in patients with chronic lymphocytic leukemia treated with lenalidomide. Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Blood (2019) 134:675. doi: 10.1182/blood-2019-129392, 44. AMLCG Study Group. Multiple studies have reported that the presence of TP53 mutations produce low response to treatments, significant rate of relapses, and poor prognosis (60, 61). Therefore, novel drugs that target mutant p53 or the critical pathways activated by p53 mutation are highly promising for effective treatment of many cancers, including AML and probably these agents represent the future landscape in AML scenario.