title: Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc.
abstract: Therapy-related myeloid neoplasms (t-MN) are a late complication of the successful use of cytotoxic therapy for patients with cancer. A heterozygous deletions of the long arm of chromosome 5 [del(5q)], observed in 40% of patients, is associated with prior exposure to alkylating agents, and a high frequency of TP53 loss or mutation. In previous studies, we demonstrated that haploinsufficiency of 2 del(5q) genes, Egr1, and Apc, individually play a role in the pathogenesis of hematologic disease in mice. We now show that loss of one copy of Egr1 or Tp53 in an Apc haploinsufficient background (Apc (del/+)) accelerated the development of a macrocytic anemia with monocytosis, early features of t-MN. The development of anemia was significantly accelerated by treatment of mice with the alkylating agent, N-ethyl-N-nitrosourea (ENU), regardless of the levels of expression of Egr1 and Tp53. Transplantation of either wild type; Egr1(+/-); Tp53(+/-); Apc(del/+); or Egr1(+/-), Apc(del/+) bone marrow cells into lethally irradiated Apc(del/+) recipients resulted in rapid development of anemia that was further accelerated by administration of ENU to recipients, demonstrating that the Apc(del/+)-induced anemia was cell extrinsic and potentiated by ENU mutagenesis. These data emphasize the synergistic role of cell intrinsic and cell extrinsic (microenvironment) factors in the pathogenesis of t-MN, and raise awareness of the deleterious effects of cytotoxic therapy on the stromal microenvironment.
authors.affiliation: Department of Medicine.
authors.forename: Angela
authors.initials: A
authors.lastname: Stoddart
authors.forename: Jianghong
authors.initials: J
authors.lastname: Wang
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fernald
authors.forename: Theodore
authors.initials: T
authors.lastname: Karrison
authors.forename: John
authors.initials: J
authors.lastname: Anastasi
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000483:Alleles; D000748:Anemia, Macrocytic / Q000139:chemically induced / Q000235:genetics / Q000401:mortality; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001853:Bone Marrow / Q000187:drug effects; D060833:Cellular Microenvironment / Q000187:drug effects; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D051766:Early Growth Response Protein 1 / Q000235:genetics*; D004900:Erythroblasts / Q000166:cytology / Q000378:metabolism; D004920:Erythropoiesis / Q000235:genetics; D005038:Ethylnitrosourea / Q000009:adverse effects; D005804:Genes, Lethal; D005838:Genotype; D057895:Haploinsufficiency; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013154:Spleen / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051766:Early Growth Response Protein 1; D016159:Tumor Suppressor Protein p53; D005038:Ethylnitrosourea