title: CBL-B is required for leukemogenesis mediated by BCR-ABL through negative regulation of bone marrow homing.
abstract: BCR-ABL induces chronic myeloid leukemia (CML) through the aberrant regulation of multiple signaling substrates. Previous research has shown that BCR-ABL mediates down-modulation of CBL-B protein levels. A murine bone marrow transplantation (BMT) study was performed to assess the contribution of Cbl-b to BCR-ABL-induced disease. The predominant phenotype in the Cbl-b(-/-) recipients was a CML-like myeloproliferative disease (MPD) similar to that observed in the wild-type animals, but with a longer latency, diminished circulating leukocyte numbers and reduced spleen weights. Despite the decreased leukemic burden in comparison to their wild-type counterparts, the Cbl-b(-/-) animals displayed enhanced numbers of Gr-1(+)/Mac-1(+) spleen cells and neutrophilia. On the basis of prior evidence of CBL-B-dependent motility toward SDF-1α, we hypothesized that Cbl-b deficiency might impair bone marrow localization during transplantation. Homing experiments showed reduced migration of Cbl-b(-/-) cells to the bone marrow. Intrafemoral transplantation of BCR-ABL-transduced Cbl-b(-/-) cells revealed equivalent latency of disease development to the wild-type transplants, supporting the conclusion that Cbl-b deficiency diminishes homing of leukemic cells to the bone marrow, and perturbs the proliferation of BCR-ABL-expressing malignant clones during CML development.
authors.affiliation: Ontario Cancer Institute, 610 University Avenue, Toronto, ON, Canada.
authors.forename: K M
authors.initials: KM
authors.lastname: Badger-Brown
authors.forename: L C
authors.initials: LC
authors.lastname: Gillis
authors.forename: M L
authors.initials: ML
authors.lastname: Bailey
authors.forename: J M
authors.initials: JM
authors.lastname: Penninger
authors.forename: D L
authors.initials: DL
authors.lastname: Barber
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000209:etiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050721:Proto-Oncogene Proteins c-cbl / Q000502:physiology*; D019707:Receptors, Chemokine / Q000032:analysis
chemical_list: C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D050721:Proto-Oncogene Proteins c-cbl; D016044:Fusion Proteins, bcr-abl; C493849:Cbl protein, mouse