N-ethyl-N-nitrosourea (ENU) alters cytokine expression in the bone marrow modifying the marrow microenvironment to develop leukemia

Abstract

Cytokines in the bone marrow (BM) microenvironment play a pivotal role in regulating hematopoiesis. In hematological disease including leukemia, altered levels of BM cytokines highlight the significance of its signaling in leukemogenesis. Elucidating the dynamics of cytokine expression and signaling in the BM is thus essential for uncovering new therapeutic targets and improving treatment outcomes. This study hypothesizes that chronic changes in cytokine expression within the BM drive the development of leukemia. To test this hypothesis, we designed a longitudinal animal experiment wherein mice were injected with the carcinogen N-ethyl-N-nitrosourea (ENU) and subsequently sacrificed at 10 distinct and even time points spanning 2-20 weeks after ENU exposure. Comparative analysis of BM samples from ENU-injected and normal mice revealed significant alterations in cytokine expression, oxidative stress, and key proteins involved in DNA synthesis and cell cycle regulation. The dynamic changes in the expression of studied cytokines, oxidative stress balance, and proteins like PCNA and NF-κB indicate modulation of the marrow microenvironment. These changes, which vary with exposure time, might impact the cellular processes in hematopoietic stem cells (HSCs) to give rise to leukemia. This study investigated the dynamic expression of hematopoietic and inflammatory genes, hinting at the critical role of deregulated cytokine expression in leukemia induction. The outcomes of this study will inform future research aimed at elucidating cytokine interactions in leukemogenesis.

Keywords: Bone marrow; Cytokines; ENU; Hematopoiesis; Leukemia; Oxidative stress.