Cytotoxic Therapy-Induced Effects on Both Hematopoietic and Marrow Stromal Cells Promotes Therapy-Related Myeloid Neoplasms

Blood Cancer Discov. 2020 Jul;1(1):32-47. doi: 10.1158/2643-3230.BCD-19-0028.

Abstract

Therapy-related myeloid neoplasms (t-MNs) 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.

Keywords: TP53; del(5q); mesenchymal stromal cells; senescence; therapy-related myeloid neoplasms.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating* / adverse effects
  • Antineoplastic Agents, Alkylating* / therapeutic use
  • Bone Marrow*
  • Chromosome Deletion
  • Genes, p53
  • Leukemia, Myeloid* / chemically induced
  • Leukemia, Myeloid* / genetics
  • Mice
  • Neoplasms, Second Primary* / chemically induced
  • Neoplasms, Second Primary* / genetics
  • Stromal Cells
  • Tumor Microenvironment / genetics

Substances

  • Antineoplastic Agents, Alkylating