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Exp Hematol. 2018 Mar;59:9-13. doi: 10.1016/j.exphem.2017.12.004. Epub 2017 Dec 15.

A vicious interplay between genetic and environmental insults in the etiology of blood cancers.

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Department of Biomedical and Neuromotorial Sciences, Alma Mater University, Bologna, Italy; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (ISMMS), New York, New York. Electronic address:


Over the years, the etiology of cancer has been attributed alternatively to genetic and environmental insults. According to the genetic hypothesis, cancer cells arise from the acquisition of mutations that dysregulate the intrinsic mechanisms controlling normal cell growth and survival. In contrast, the environmental hypothesis holds that cancer can be caused by multiple extrinsic challenges that alter normal tissue homeostasis, but may not necessarily involve mutations. It is, however, quite possible that these two mechanisms are not mutually exclusive. According to this third hypothesis, environmental challenges, by mechanisms still poorly understood, may act by imposing a selection pressure that confers a proliferative advantage on cells carrying specific driver mutations, leading to disease initiation. The authors of a brief report published in this journal (Exp Hematol. 2017;56:1-6) tested this third hypothesis experimentally and provide new evidence that chronic inflammation, by increasing tumor necrosis factor (TNF)-α, may positively select malignant hematopoietic stem cells (HSCs) carrying loss-of-function TET2 mutations that switch the TNF-α signaling responses to activate proliferation rather than inducing quiescence. Furthermore, these mutations skew hematopoietic differentiation toward the myelomonocytic lineage and the output of macrophages producing TNF-α constitutively, promoting further environment-independent expansion of the malignant HSCs. These findings support a model in which the formation of a malignant population is triggered by a vicious interplay between genetic (TET2 mutations) and environmental (inflammation) insults, suggesting the need for strategies that target both the malignant cells and their environment.

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