title: 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.
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.
authors.affiliation: Department of Internal Medicine, Division of Hematology and Oncology, University of California Davis Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA, United States of America.
authors.forename: Brian A
authors.identifier: http://orcid.org/0000-0002-4921-5809
authors.initials: BA
authors.lastname: Jonas
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Carl
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Dita
authors.initials: D
authors.lastname: Gratzinger
authors.affiliation: Department of Medicine, Division of Hematology, Cancer Institute, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, United States of America.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D000477:Alkylating Agents; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D004195:Disease Models, Animal; D005038:Ethylnitrosourea; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced* / Q000473:pathology; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000139:chemically induced* / Q000473:pathology; D016609:Neoplasms, Second Primary / Q000139:chemically induced* / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*
chemical_list: D000477:Alkylating Agents; D005038:Ethylnitrosourea