Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia.
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| Title: | Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia. |
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| Authors: | Kogan, Aksinija A.1,2, Topper, Michael J.3, Dellomo, Anna J.1,2, Stojanovic, Lora1,2, McLaughlin, Lena J.1,2, Creed, T. Michael4, Eberly, Christian L.4, Kingsbury, Tami J.1,4,5, Baer, Maria R.1,6, Kessler, Michael D.3, Baylin, Stephen B.3,7 sbaylin@jhmi.edu, Rassool, Feyruz V.1,2 frassool@som.umaryland.edu |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 7/5/2022, Vol. 119 Issue 27, p1-12. 32p. |
| Subjects: | Acute myeloid leukemia, Poly ADP ribose, Fireproofing agents, Endogenous retroviruses, Cancer genes, Genetic counseling |
| Abstract: | DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in TP53, associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with wild-type (WT) TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT TP53, DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling that we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi + PARPi treatment, and also DNMTi combinations with immune therapies, suggesting a personalized approach that statifies by TP53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 157881536 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Kogan%2C+Aksinija+A%2E%22">Kogan, Aksinija A.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Topper%2C+Michael+J%2E%22">Topper, Michael J.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Dellomo%2C+Anna+J%2E%22">Dellomo, Anna J.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Stojanovic%2C+Lora%22">Stojanovic, Lora</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22McLaughlin%2C+Lena+J%2E%22">McLaughlin, Lena J.</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Creed%2C+T%2E+Michael%22">Creed, T. Michael</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Eberly%2C+Christian+L%2E%22">Eberly, Christian L.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Kingsbury%2C+Tami+J%2E%22">Kingsbury, Tami J.</searchLink><relatesTo>1,4,5</relatesTo><br /><searchLink fieldCode="AR" term="%22Baer%2C+Maria+R%2E%22">Baer, Maria R.</searchLink><relatesTo>1,6</relatesTo><br /><searchLink fieldCode="AR" term="%22Kessler%2C+Michael+D%2E%22">Kessler, Michael D.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Baylin%2C+Stephen+B%2E%22">Baylin, Stephen B.</searchLink><relatesTo>3,7</relatesTo><i> sbaylin@jhmi.edu</i><br /><searchLink fieldCode="AR" term="%22Rassool%2C+Feyruz+V%2E%22">Rassool, Feyruz V.</searchLink><relatesTo>1,2</relatesTo><i> frassool@som.umaryland.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 7/5/2022, Vol. 119 Issue 27, p1-12. 32p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Acute+myeloid+leukemia%22">Acute myeloid leukemia</searchLink><br /><searchLink fieldCode="DE" term="%22Poly+ADP+ribose%22">Poly ADP ribose</searchLink><br /><searchLink fieldCode="DE" term="%22Fireproofing+agents%22">Fireproofing agents</searchLink><br /><searchLink fieldCode="DE" term="%22Endogenous+retroviruses%22">Endogenous retroviruses</searchLink><br /><searchLink fieldCode="DE" term="%22Cancer+genes%22">Cancer genes</searchLink><br /><searchLink fieldCode="DE" term="%22Genetic+counseling%22">Genetic counseling</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: DNA methyltransferase inhibitors (DNMTis) reexpress hypermethylated genes in cancers and leukemias and also activate endogenous retroviruses (ERVs), leading to interferon (IFN) signaling, in a process known as viral mimicry. In the present study we show that in the subset of acute myeloid leukemias (AMLs) with mutations in TP53, associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING-dependent manner. We previously reported that in solid tumors poly ADP ribose polymerase inhibitors (PARPis) combined with DNMTis to induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with wild-type (WT) TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with WT TP53, DNMTis alone have no effect. While combining DNMTis with PARPis increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling that we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi + PARPi treatment, and also DNMTi combinations with immune therapies, suggesting a personalized approach that statifies by TP53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.2123227119 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 32 StartPage: 1 Subjects: – SubjectFull: Acute myeloid leukemia Type: general – SubjectFull: Poly ADP ribose Type: general – SubjectFull: Fireproofing agents Type: general – SubjectFull: Endogenous retroviruses Type: general – SubjectFull: Cancer genes Type: general – SubjectFull: Genetic counseling Type: general Titles: – TitleFull: Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Kogan, Aksinija A. – PersonEntity: Name: NameFull: Topper, Michael J. – PersonEntity: Name: NameFull: Dellomo, Anna J. – PersonEntity: Name: NameFull: Stojanovic, Lora – PersonEntity: Name: NameFull: McLaughlin, Lena J. – PersonEntity: Name: NameFull: Creed, T. Michael – PersonEntity: Name: NameFull: Eberly, Christian L. – PersonEntity: Name: NameFull: Kingsbury, Tami J. – PersonEntity: Name: NameFull: Baer, Maria R. – PersonEntity: Name: NameFull: Kessler, Michael D. – PersonEntity: Name: NameFull: Baylin, Stephen B. – PersonEntity: Name: NameFull: Rassool, Feyruz V. IsPartOfRelationships: – BibEntity: Dates: – D: 05 M: 07 Text: 7/5/2022 Type: published Y: 2022 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 119 – Type: issue Value: 27 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
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