title: Induction of histiocytic sarcoma in mouse skeletal muscle.
abstract: Myeloid sarcomas are extramedullary accumulations of immature myeloid cells that may present with or without evidence of pathologic involvement of the bone marrow or peripheral blood, and often coincide with or precede a diagnosis of acute myeloid leukemia (AML). A dearth of experimental models has hampered the study of myeloid sarcomas and led us to establish a new system in which tumor induction can be evaluated in an easily accessible non-hematopoietic tissue compartment. Using ex-vivo transduction of oncogenic Kras(G12V) into p16/p19(-/-) bone marrow cells, we generated transplantable leukemia-initiating cells that rapidly induced tumor formation in the skeletal muscle of immunocompromised NOD.SCID mice. In this model, murine histiocytic sarcomas, equivalent to human myeloid sarcomas, emerged at the injection site 30-50 days after cell implantation and consisted of tightly packed monotypic cells that were CD48+, CD47+ and Mac1+, with low or absent expression of other hematopoietic lineage markers. Tumor cells also infiltrated the bone marrow, spleen and other non-hematopoietic organs of tumor-bearing animals, leading to systemic illness (leukemia) within two weeks of tumor detection. P16/p19(-/-); Kras(G12V) myeloid sarcomas were multi-clonal, with dominant clones selected during secondary transplantation. The systemic leukemic phenotypes exhibited by histiocytic sarcoma-bearing mice were nearly identical to those of animals in which leukemia was introduced by intravenous transplantation of the same donor cells. Moreover, murine histiocytic sarcoma could be similarly induced by intramuscular injection of MLL-AF9 leukemia cells. This study establishes a novel, transplantable model of murine histiocytic/myeloid sarcoma that recapitulates the natural progression of these malignancies to systemic disease and indicates a cell autonomous leukemogenic mechanism.
authors.affiliation: Howard Hughes Medical Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute, and Joslin Diabetes Center, Cambridge, Massachusetts, USA.
authors.forename: Jianing
authors.initials: J
authors.lastname: Liu
authors.forename: Simone
authors.initials: S
authors.lastname: Hettmer
authors.forename: Michael D
authors.initials: MD
authors.lastname: Milsom
authors.forename: Inga
authors.initials: I
authors.lastname: Hofmann
authors.forename: Frederic
authors.initials: F
authors.lastname: Hua
authors.forename: Christine
authors.initials: C
authors.lastname: Miller
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002999:Clone Cells; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000378:metabolism; D004273:DNA, Neoplasm / Q000235:genetics; D054747:Histiocytic Sarcoma / Q000235:genetics / Q000473:pathology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018482:Muscle, Skeletal / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D009857:Oncogenes / Q000235:genetics; D010641:Phenotype; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)