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A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1
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| Zeitschriftentitel: | Cancer Discovery |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , |
| In: | Cancer Discovery, 9, 2019, 7, S. 962-979 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
American Association for Cancer Research (AACR)
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| Schlagwörter: |
| author_facet |
Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. |
|---|---|
| author |
Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. |
| spellingShingle |
Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. Cancer Discovery A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 Oncology |
| author_sort |
loizou, evangelia |
| spelling |
Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. 2159-8274 2159-8290 American Association for Cancer Research (AACR) Oncology http://dx.doi.org/10.1158/2159-8290.cd-18-1391 <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 813</jats:p> </jats:sec> A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 Cancer Discovery |
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American Association for Cancer Research (AACR), 2019 |
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American Association for Cancer Research (AACR), 2019 |
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| title |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_unstemmed |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_full |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_fullStr |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_full_unstemmed |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_short |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_sort |
a gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor foxh1 |
| topic |
Oncology |
| url |
http://dx.doi.org/10.1158/2159-8290.cd-18-1391 |
| publishDate |
2019 |
| physical |
962-979 |
| description |
<jats:title>Abstract</jats:title>
<jats:sec>
<jats:title />
<jats:p>Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer.</jats:p>
</jats:sec>
<jats:sec>
<jats:title>Significance:</jats:title>
<jats:p>Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.</jats:p>
<jats:p>This article is highlighted in the In This Issue feature, p. 813</jats:p>
</jats:sec> |
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| author | Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao, Kinalis, Savvas, Bagger, Frederik O., Kastenhuber, Edward R., Durham, Benjamin H., Lowe, Scott W. |
| author_facet | Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao, Kinalis, Savvas, Bagger, Frederik O., Kastenhuber, Edward R., Durham, Benjamin H., Lowe, Scott W., Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao, Kinalis, Savvas, Bagger, Frederik O., Kastenhuber, Edward R., Durham, Benjamin H., Lowe, Scott W. |
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| description | <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 813</jats:p> </jats:sec> |
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| imprint_str_mv | American Association for Cancer Research (AACR), 2019 |
| institution | DE-D275, DE-Bn3, DE-Brt1, DE-Zwi2, DE-D161, DE-Gla1, DE-Zi4, DE-15, DE-Pl11, DE-Rs1, DE-105, DE-14, DE-Ch1, DE-L229 |
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| spelling | Loizou, Evangelia Banito, Ana Livshits, Geulah Ho, Yu-Jui Koche, Richard P. Sánchez-Rivera, Francisco J. Mayle, Allison Chen, Chi-Chao Kinalis, Savvas Bagger, Frederik O. Kastenhuber, Edward R. Durham, Benjamin H. Lowe, Scott W. 2159-8274 2159-8290 American Association for Cancer Research (AACR) Oncology http://dx.doi.org/10.1158/2159-8290.cd-18-1391 <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats:p>Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 813</jats:p> </jats:sec> A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 Cancer Discovery |
| spellingShingle | Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao, Kinalis, Savvas, Bagger, Frederik O., Kastenhuber, Edward R., Durham, Benjamin H., Lowe, Scott W., Cancer Discovery, A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1, Oncology |
| title | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_full | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_fullStr | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_full_unstemmed | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_short | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| title_sort | a gain-of-function p53-mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor foxh1 |
| title_unstemmed | A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1 |
| topic | Oncology |
| url | http://dx.doi.org/10.1158/2159-8290.cd-18-1391 |