Abstract
Therapy-related myeloid neoplasms (t-MN) following treatment with alkylating agents are characterized by a del(5q), complex karyotypes, alterations of TP53, and a dismal prognosis. To decipher the molecular pathway(s) leading to the pathogenesis of del(5q) t-MN and the effect(s) of cytotoxic therapy on the marrow microenvironment, we developed a mouse model with loss of two key del(5q) genes, EGR1 and APC, in hematopoietic cells. We used the well-characterized drug, N-ethyl-N-nitrosurea (ENU), to demonstrate that alkylating agent exposure of stromal cells in the microenvironment increases the incidence of myeloid disease. In addition, loss of Trp53 with Egr1 and Apc was required to drive the development of a transplantable leukemia, and accompanied by the acquisition of somatic mutations in DNA damage response genes. ENU treatment of mesenchymal stromal cells induced cellular senescence and led to the acquisition of a senescence-associated secretory phenotype, which may be a critical microenvironmental alteration in the pathogenesis of myeloid neoplasms.
This study challenges the historic view that prior cytotoxic therapy targets only hematopoietic cells and shows that chemotherapy-induced alterations to the microenvironment contribute to myeloid neoplasms in a model of del(5q) t-MN. The DNA damage response in hematopoietic cells and senescence of stromal cells are identified as potential therapeutic targets.
See related commentary by Shannon and Link, p. 10.
This article is highlighted in the In This Issue feature, p. 5