@article{2efe66ae5c0e4fc3b007f8beed7147d5,
title = "Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness versus Lineage Output in Dnmt3a-Mutant Clonal Hematopoiesis",
abstract = "Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regu-lated is unclear. Using a mouse model of a clonal hematopoiesis–associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted in the overproduction of mutant myeloid cells without altering HSC fitness. These results nominate TNFR1 as a target to reduce clonal hematopoiesis and the risk of associated diseases and support a model in which clone size and mature blood lineage production can be independently controlled to modulate favorable and unfavorable clonal hematopoiesis outcomes. SIGNIFICANCE: Through the identification and dissection of TNFα signaling as a key driver of murine Dnmt3a-mutant hematopoiesis, we report the discovery that clone size and production of specific mature blood cell types can be independently regulated.",
author = "Sanmiguel, {Jennifer M.} and Elizabeth Eudy and Loberg, {Matthew A.} and Young, {Kira A.} and Mistry, {Jayna J.} and Mujica, {Kristina D.} and Schwartz, {Logan S.} and Stearns, {Timothy M.} and Challen, {Grant A.} and Trowbridge, {Jennifer J.}",
note = "Funding Information: J.M. SanMiguel reports grants from the NIH and from the American Society of Hematology during the conduct of the study, as well as a patent for D21-017-USPROV1 pending. L.S. Schwartz reports grants—Burroughs Wellcome Training Fellow and Ruth L. Kirschstein Predoctoral Individual National Research Service Award—outside the submitted work. J.J. Trowbridge reports grants from the NIH, the EvansMDS Foundation, the Leukemia & Lymphoma Society, the American Society of Hematology, the Ellison Medical Foundation, V the Foundation, and the Maine Cancer Foundation during the conduct of the study; other support from H3 Biomedicine outside the submitted work; and a patent for D21-017-USPROV1 pending and a patent for US20130209430A1 issued, licensed, and with royalties paid from Fate Therapeutics. No disclosures were reported by the other authors. Funding Information: We thank all members of the Trowbridge lab for their help with experimental support and manuscript editing and Scientific Services at The Jackson Laboratory. We thank Ross Levine, Coleman Lindsley, and Michael Rauh for discussions and input, and Dan Landau and Neville Dusaj for providing single-cell expression data from human DNMT3A-mutant clonal hematopoiesis samples. This work was supported by NIH U01AG077925 (J.J. Trowbridge), NIH R01DK118072 (J.J. Trowbridge), NIH R01AG069010 (J.J. Trowbridge), and an Evans-MDS Discovery Research Grant (J.J. Trowbridge). This study was supported in part by The Jackson Laboratory{\textquoteright}s Cancer Center Support Grant NIH P30CA034196. L.S. Schwartz was supported by NIH F31DK127573. J.M. SanMiguel was supported by NIH T32AG062409, NIH T32HD007065, and an American Society of Hematology Scholar Award. J.J. Mistry was supported by a JAX Scholar award. G.A. Challen and J.J. Trowbridge are scholars of the Leukemia & Lymphoma Society. G.A. Challen was supported by NIH R01DK124883. Publisher Copyright: {\textcopyright} 2022 The Authors; Published by the American Association for Cancer Research.",
year = "2022",
month = dec,
day = "1",
doi = "10.1158/2159-8290.CD-22-0086",
language = "English",
volume = "12",
pages = "2763--2773",
journal = "Cancer Discovery",
issn = "2159-8274",
number = "12",
}