RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis

Nana Adjoa Ben-Crentsil; Wazim Mohammed Ismail; Maria E Balasis; Hannah Newman; Ariel Quintana; Moritz Binder; Traci Kruer; Surendra Neupane; Meghan C Ferrall-Fairbanks; Jenna Fernandez; Terra L Lasho; Christy M Finke; Mohammed L Ibrahim; Kathy L McGraw; Michael Wysota; Amy L Aldrich; Christopher B Ryder; Christopher T Letson; Joshua Traina; Amy F McLemore; Nathalie Droin; Aditi Shastri; Seongseok Yun; Eric Solary; David A Sallman; Amer A Beg; Li Ma; Alexandre Gaspar-Maia; Mrinal M Patnaik; Eric Padron

doi:10.1158/2159-8290.CD-24-0093

RNA Shielding of p65 Is Required to Potentiate Oncogenic Inflammation in TET2-Mutated Clonal Hematopoiesis

Cancer Discov. 2024 Dec 2;14(12):2509-2531. doi: 10.1158/2159-8290.CD-24-0093.

Authors

Nana Adjoa Ben-Crentsil¹, Wazim Mohammed Ismail², Maria E Balasis¹, Hannah Newman¹, Ariel Quintana¹, Moritz Binder³, Traci Kruer¹, Surendra Neupane¹, Meghan C Ferrall-Fairbanks^{4

5}, Jenna Fernandez³, Terra L Lasho³, Christy M Finke³, Mohammed L Ibrahim^{6

7}, Kathy L McGraw⁸, Michael Wysota⁹, Amy L Aldrich¹, Christopher B Ryder¹, Christopher T Letson¹, Joshua Traina¹, Amy F McLemore¹, Nathalie Droin¹⁰, Aditi Shastri⁹, Seongseok Yun¹, Eric Solary¹⁰, David A Sallman¹, Amer A Beg⁶, Li Ma¹¹, Alexandre Gaspar-Maia², Mrinal M Patnaik³, Eric Padron¹

Affiliations

¹ Department of Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, Florida.
² Epigenomics Program, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota.
³ Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.
⁴ J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
⁵ University of Florida Health Cancer Center, University of Florida, Gainesville, Florida.
⁶ Department of Immunology, Moffitt Cancer Center, Tampa, Florida.
⁷ Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
⁸ National Institutes of Health, Bethesda, Maryland.
⁹ Department of Medical Oncology, Montefiore Medical Center, Bronx, New York.
¹⁰ NSERM U1287, Gustave Roussy Cancer Center, Villejuif, France.
¹¹ Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.

PMID: 39189614
PMCID: PMC11611684 (available on 2025-06-02)
DOI: 10.1158/2159-8290.CD-24-0093

Abstract

This work identifies MALAT1 as a requisite downstream effector of oncogenic feedforward inflammatory circuits necessary for the development of TET2-mutated CH and fulminant myeloid malignancy. We elucidate a novel mechanism by which MALAT1 "shields" p65 from dephosphorylation to potentiate this circuit and nominate MALAT1 inhibition as a future therapeutic strategy.

MeSH terms

Animals
Clonal Hematopoiesis*
DNA-Binding Proteins* / genetics
Dioxygenases*
Humans
Inflammation* / genetics
Mice
Mutation
Proto-Oncogene Proteins* / genetics
RNA, Long Noncoding / genetics
Transcription Factor RelA / genetics
Transcription Factor RelA / metabolism

Substances

Dioxygenases
Proto-Oncogene Proteins
DNA-Binding Proteins
TET2 protein, human
RNA, Long Noncoding
Transcription Factor RelA

Abstract

MeSH terms

Substances

Grants and funding