Alkylator-Induced and Patient-Derived Xenograft Mouse Models of Therapy-Related Myeloid Neoplasms Model Clinical Disease and Suggest the Presence of Multiple Cell Subpopulations with Leukemia Stem Cell Activity

PLoS One. 2016 Jul 18;11(7):e0159189. doi: 10.1371/journal.pone.0159189. eCollection 2016.

Abstract

Acute myeloid leukemia (AML) is a heterogeneous group of aggressive bone marrow cancers arising from transformed hematopoietic stem and progenitor cells (HSPC). Therapy-related AML and MDS (t-AML/MDS) comprise a subset of AML cases occurring after exposure to alkylating chemotherapy and/or radiation and are associated with a very poor prognosis. Less is known about the pathogenesis and disease-initiating/leukemia stem cell (LSC) subpopulations of t-AML/MDS compared to their de novo counterparts. Here, we report the development of mouse models of t-AML/MDS. First, we modeled alkylator-induced t-AML/MDS by exposing wild type adult mice to N-ethyl-N-nitrosurea (ENU), resulting in several models of AML and MDS that have clinical and pathologic characteristics consistent with human t-AML/MDS including cytopenia, myelodysplasia, and shortened overall survival. These models were limited by their inability to transplant clinically aggressive disease. Second, we established three patient-derived xenograft models of human t-AML. These models led to rapidly fatal disease in recipient immunodeficient xenografted mice. LSC activity was identified in multiple HSPC subpopulations suggesting there is no canonical LSC immunophenotype in human t-AML. Overall, we report several new t-AML/MDS mouse models that could potentially be used to further define disease pathogenesis and test novel therapeutics.

MeSH terms

  • Alkylating Agents*
  • Animals
  • Bone Marrow Cells / drug effects
  • Bone Marrow Cells / pathology
  • Disease Models, Animal
  • Ethylnitrosourea*
  • Humans
  • Leukemia, Myeloid, Acute / chemically induced*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Myelodysplastic Syndromes / chemically induced*
  • Myelodysplastic Syndromes / pathology
  • Neoplasms, Second Primary / chemically induced*
  • Neoplasms, Second Primary / pathology
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / pathology*

Substances

  • Alkylating Agents
  • Ethylnitrosourea