Chronic TNF in the aging microenvironment exacerbates Tet2 loss-of-function myeloid expansion

被引:2
作者
Quin, Candice [1 ,2 ,3 ]
DeJong, Erica N. [1 ,2 ]
McNaughton, Amy J. M. [4 ]
Buttigieg, Marco M. [4 ]
Basrai, Salman [5 ,6 ]
Abelson, Sagi [5 ,6 ]
Larche, Maggie J. [1 ]
Rauh, Michael J. [4 ]
Bowdish, Dawn M. E. [1 ,2 ]
机构
[1] McMaster Univ, Fac Hlth Sci, Dept Med, Hamilton, ON, Canada
[2] St Josephs Healthcare Hamilton, Firestone Inst Resp Hlth, Hamilton, ON, Canada
[3] Univ Aberdeen, Inst Med Sci, Sch Med Med Sci & Nutr, Aberdeen, Scotland
[4] Queens Univ, Fac Hlth Sci, Dept Pathol & Mol Med, Kingston, ON, Canada
[5] Ontario Inst Canc Res, Toronto, ON, Canada
[6] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada
基金
加拿大健康研究院;
关键词
HEMATOPOIETIC STEM-CELLS; CLONAL HEMATOPOIESIS; AGE; DNMT3A; INFLAMMATION; MUTATIONS; MEMORY; RISK;
D O I
10.1182/bloodadvances.2023011833
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- -/- genotypes reconstituted with WT CD45.1* * and Tet2 - / - CD45.2 * HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2 - / - cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- -/- recipient mice, suggesting that TNF signaling is essential for the expansion Tet2- mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, , may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-- mutant CHIP.
引用
收藏
页码:4169 / 4180
页数:12
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