A dominant-negative effect drives selection of
            <i>TP53</i>
            missense mutations in myeloid malignancies

Boettcher, Steffen; Miller, Peter G.; Sharma, Rohan; McConkey, Marie; Leventhal, Matthew; Krivtsov, Andrei V.; Giacomelli, Andrew O.; Wong, Waihay J.; Kim, Jesi; Chao, Sherry; Kurppa, Kari J.; Yang, Xiaoping; Milenkowic, Kirsten; Piccioni, Federica; Root, David E.; Rücker, Frank G.; Flamand, Yael; Neuberg, Donna; Lindsley, R. Coleman; Jänne, Pasi A.; Hahn, William C.; Jacks, Tyler; Döhner, Hartmut; Armstrong, Scott A.; Ebert, Benjamin L.

doi:10.1126/science.aax3649

Cited by 322 publications

(255 citation statements)

References 52 publications

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“…We also observed dominant negative effects for many p53 missense mutations (Fig. 3C), which is consistent with recent findings by Boettcher et al (Boettcher et al, 2019). This led to recognitions of amino acid residues and structural regions crucial for p53 function (Fig.…”

Section: Functional Landscape Of P53 Mutations In Human Cancersupporting

confidence: 92%

Defining relative mutational difficulty to understand cancer formation and prevention

Shan

et al. 2019

Preprint

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Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancerpromoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Furthermore, mutational difficulty analysis also points to potential means of cancer prevention. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such parameter, we can bring new angles to understanding cancer formation and prevention.

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Section: Functional Landscape Of P53 Mutations In Human Cancersupporting

confidence: 92%

Defining relative mutational difficulty to understand cancer formation and prevention

Shan

et al. 2019

Preprint

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“…In fact, TP53 alterations in AML hold prognostic value for response to chemotherapy and survival. 21,111,112 In a functional study, 79 mouse models of AML1-ETO-and MLL-ENL-fusion-driven AML were treated with chemotherapy to assess their respective sensitivities. Notably, these mouse models differed in a robust activation of TP53 network genes in the case of AML1-ETO mice, in contrast to an attenuation of the TP53-network in the MLL-ENL-driven disease.…”

Section: The Role Of Tp53 In Drug Response In Amlmentioning

confidence: 99%

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Barbosa

Adams

et al. 2019

Genes Chromosomes & Cancer

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The tumor suppressor gene TP53 is one of the most frequently mutated genes in human cancer. The central role of the TP53 protein in several fundamental processes such as cancer, aging, senescence, and DNA repair has ensured enormous attention. However, the role of TP53 in acute myeloid leukemia (AML) is enigmatic. Unlike many other human cancers, a vast majority of AMLs display no genomic TP53 alterations. There is now growing appreciation of the fact that the unaltered TP53 status of tumor cells can be exploited therapeutically. As most AMLs have an intact TP53 gene, its physiological tumor‐suppressive roles could be harnessed. Therefore, the use of pharmacological activators of the TP53 pathway may provide clinical benefit in AML. Conversely, even though the frequency of TP53 mutations in AML is substantially lower than in other human cancers, TP53 mutations are associated with chemoresistance and high risk of relapse. In patients with TP53 mutations, these alterations may lead to novel, selective vulnerabilities, creating opportunities for therapeutic targeting of TP53 mutant AML. The mutational status of TP53 therefore poses challenges and opportunities in terms of advancing effective treatment strategies in AML. An increasing armamentarium of small‐molecule activators of the TP53 pathway, and a growing understanding of molecular pathways triggered by mutant TP53 have accelerated efforts aimed at targeting TP53 function in AML. In combination with standard AML chemotherapy or emerging targeted therapies, pharmacological targeting of the TP53 pathway may provide therapeutic benefit in AML.

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“…Importantly, we find in our CRC model that the remaining WT allele in heterozygous tumors is fully activatable, excluding a dominant-negative effect (DNE) by the counterpart mutp53 allele. Although DNE is a likely key driver behind the p53 mutational spectrum in myeloid malignancies 72 , many missense mutants are highly inefficient in their ability to exert DNE in epithelial carcinomas and sarcomas, including the hotspot p53 R248Q allele 9, 31, 56, 73 . We and others speculate that for DNE to occur in solid tumors, the MUT/WT protein ratio has to greatly shift in favor of MUT 56, 74 .…”

Section: Discussionmentioning

confidence: 99%

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

Sener

Stender

Klemke

et al. 2020

Preprint

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HIGHLIGHTS 14 15• heterozygous p53 R248Q/+ tumors retain p53 transcriptional activity in a mouse model of 16 colorectal cancer (CRC) 17• wildtype p53 actively represses the tumor-promoting HSF1-regulated chaperone system 18 and proteotoxic stress response 19• the repressive WTp53 -HSF1 axis creates a selective pressure for WTp53 loss-of-20 heterozygosity in CRC tumors 21• p53 loss-of-heterozygosity enables stabilization of the gain-of-function p53 R248Q mutant 22 protein which in turn enables CRC invasion 23 24 25 26 27 28 29 30 2 31 Abstract 32A prerequisite for gain-of-function (GOF) p53 missense mutants (mutp53) is protein 33 stabilization. Moreover, a prerequisite for mutp53 stabilization is loss of the remaining wildtype 34 (WT) p53 allele (loss-of-heterozygosity, p53LOH) in mutp53/+ tumors. Thus, GOF, mutp53 35 stabilization and p53LOH are strictly linked. However, the driving force for p53LOH is unknown. 36Typically, heterozygous tumors are an instable transition state. Here we identify the repressive 37WTp53-HSF1 axis as the driver of p53LOH. 38We find that the WTp53 allele in AOM/DSS-induced colorectal tumors (CRC) of p53 R248Q/+ mice 39 retains its haploid transcriptional activity. Notably, WTp53 represses heat-shock factor 1 (HSF1) 40 activity, the master transcription factor of the proteotoxic stress defense response (HSR) that is 41 ubiquitously and constitutively activated in cancer tissues. HSR is critical for stabilizing 42 oncogenic proteins including mutp53. WTp53-retaining murine CRC tumors and tumor-derived 43 organoids and human CRC cells all suppress the tumor-promoting HSF1 transcriptional 44 program. 45Mechanistically, the retained WTp53 allele activates CDKN1A/p21, leading to cell cycle 46 inhibition and suppression of the E2F target gene MLK3. MLK3 links cell cycle to the MAPK 47 stress pathway to activate the HSR response. We show that in p53 R248Q/+ tumors WTp53 48 activation by constitutive stress (emanating from proliferative/metabolic stresses and genomic 49 instability) represses MLK3, consequently inactivating the MAPK-HSF1 response necessary to 50 ensure tumor survival. This creates strong selection pressure for p53LOH which eliminates the 51 repressive WTp53-HSF1 axis and unleashes the tumor-promoting HSF1 functions, inducing 52 mutp53 stabilization and enabling invasion. 53 54 Keywords 55 mutp53, HSF1, Hsp90, Hsp70, CDK4, MLK3, MAPK, AOM/DSS, colorectal cancer, organoids, 56 Idasanutlin 57 58 59 60 RESULTS 101 p53LOH is a prerequisite for mutp53 stabilization and invasion in colorectal cancer 102Stabilization of missense mutant p53 (mutp53) proteins specifically in tumor but not normal cells 103 is a key feature and prerequisite of GOF 16, 42 . Since p53LOH is a critical prerequisite for mutp53 104 stabilization in sarcomas and breast cancer 41 , we examined mutp53 stabilization before and 105 after p53LOH in the colorectal AOM/DSS model 9 . Briefly, we combined the humanized GOF 106

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A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies

Cited by 322 publications

References 52 publications

Defining relative mutational difficulty to understand cancer formation and prevention

Defining relative mutational difficulty to understand cancer formation and prevention

The role of TP53 in acute myeloid leukemia: Challenges and opportunities

Suppression of HSF1 activity by wildtype p53 creates the driving force for p53 loss-of-heterozygosity, enabling mutant p53 stabilization and invasion

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