The Impact of Inflammation-Induced Tumor Plasticity during Myeloid Transformation

Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated preleukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carry-ing a recurrent TET2 missense mutation frequently found in patients with CH and leukemia. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single-cell transcriptomic profi ling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced infl am-matory response and the emergence of an aberrant infl ammatory monocytic cell population. The gene signature characteristic of this infl ammatory population is associated with poor prognosis in patients with AML. Our study illustrates an example of collaboration between a genetic lesion found in CH and infl ammation, leading to transformation and the establishment of blood neoplasms.

Automated summary

This article describes a novel animal model carrying a recurrent TET2 missense mutation frequently found in patients with CH and leukemia. Using single-cell transcriptomic profiling of the bone marrow, the study showed that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population.