title: Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells.
abstract: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor γ-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Askmyr
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Ågerstam
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Lilljebjörn
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Hansen
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Karlsson
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: von Palffy
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Landberg
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Högberg
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Lassen
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Rissler
authors.affiliation: Department of Molecular Medicine and Gene Therapy, Lund University and Department of Hematology and Vascular Disorders, Skåne University Hospital, Lund, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.affiliation: Department of Pathology, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Ehinger
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Järås
authors.affiliation: Department of Clinical Genetics, University and Regional Laboratories, Lund University Hospital, Lund University, Lund, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Fioretos
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005312:Fetal Blood / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000096:biosynthesis / Q000235:genetics; D064593:Heterografts; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism* / Q000473:pathology
chemical_list: C581634:BCR-ABL1 fusion protein, human; D016044:Fusion Proteins, bcr-abl