Cigarette smoke stimulates clonal expansion of Jak2V617F and Tet2-/- cells

Gajalakshmi Ramanathan; Jane H Chen; Nitya Mehrotra; Tiffany Trieu; Aaron Huang; Eduard Mas; Jessica E Monterrosa Mena; Bishop Bliss; David A Herman; Michael T Kleinman; Angela G Fleischman

doi:10.3389/fonc.2023.1210528

Cigarette smoke stimulates clonal expansion of Jak2^V617F and Tet2^-/- cells

Front Oncol. 2023 Jul 21:13:1210528. doi: 10.3389/fonc.2023.1210528. eCollection 2023.

Affiliations

¹ Department of Medicine, Division of Hematology/Oncology, University of California, Irvine, Irvine, CA, United States.
² Department of Medicine, Division of Occupational and Environmental Medicine, University of California, Irvine, Irvine, CA, United States.
³ Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA, United States.

Abstract

Introduction: Somatic mutations in myeloid growth factor pathway genes, such as JAK2, and genes involved in epigenetic regulation, such as TET2, in hematopoietic stem cells (HSCs) leads to clonal hematopoiesis of indeterminate potential (CHIP) which presents a risk factor for hematologic malignancy and cardiovascular disease. Smoking behavior has been repeatedly associated with the occurrence of CHIP but whether smoking is an environmental inflammatory stressor in promoting clonal expansion has not been investigated.

Methods: We performed in vivo smoke exposures in both wildtype (WT) mice and transplanted mice carrying Jak2^V617F mutant and Tet2 knockout (Tet-/-) cells to determine the impact of cigarette smoke (CS) in the HSC compartment as well as favoring mutant cell expansion.

Results: WT mice exposed to smoke displayed increased oxidative stress in long-term HSCs and suppression of the hematopoietic stem and progenitor compartment but smoke exposure did not translate to impaired hematopoietic reconstitution in primary bone marrow transplants. Gene expression analysis of hematopoietic cells in the bone marrow identified an imbalance between Th17 and Treg immune cells suggesting a local inflammatory environment. We also observed enhanced survival of Jak2V617F cells exposed to CS in vivo and cigarette smoke extract (CSE) in vitro. WT bone marrow hematopoietic cells from WT/Jak2V617F chimeric mice exposed to CS demonstrated an increase in neutrophil abundance and distinct overexpression of bone marrow stromal antigen 2 (Bst2) and retinoic acid early transcript 1 (Raet1) targets. Bst2 and Raet1 are indicative of increased interferon signaling and cellular stress including oxidative stress and DNA damage, respectively. In chimeric mice containing both WT and Tet2-/- cells, we observed an increased percentage of circulating mutant cells in peripheral blood post-cigarette smoke exposure when compared to pre-exposure levels while this difference was absent in air-exposed controls.

Conclusion: Altogether, these findings demonstrate that CS results in an inflamed bone marrow environment that provides a selection pressure for existing CHIP mutations such as Jak2V617F and Tet2 loss-of-function.

Keywords: cigarette smoke; clonal hematopoiesis; inflammation; myeloproliferative neoplasm; reactive oxygen species.

Grants and funding

This work was supported by the Tobacco-Related Disease Research Program (TRDRP) of the University of California, Grant Numbers T32IR5150 (A.G.F), T29IP0414 (A.G.F) and T29FT0267 (G.R), by the NCI T32 training grant NCI T32CA009054 (G.R), and the Chao Family Comprehensive Cancer Center Support Grant P30CA062203 (A.G.F.)