title: BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells.
abstract: In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL(+) Lin(-)Sca-1(+)c-kit(+) (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (Lin(-)Sca-1(-)c-kit(+)), nor mature granulocytes (CD11b(+)Gr-1(+)), nor potential stem cell niche cells (CD45(-)Ter119(-)) are able to transmit the disease or alter the phenotype. The phenotype is largely independent of BCR-ABL priming before transplantation. However, prolonged BCR-ABL expression abrogates the potential of LSK cells to induce full-blown disease in secondary recipients and increases the fraction of multipotent progenitor cells at the expense of long-term hematopoietic stem cells (LT-HSCs) in the bone marrow. BCR-ABL alters the expression of genes involved in proliferation, survival, and hematopoietic development, probably contributing to the reduced LT-HSC frequency within BCR-ABL(+) LSK cells. Reversion of BCR-ABL, or treatment with imatinib, eradicates mature cells, whereas leukemic stem cells persist, giving rise to relapsed chronic myeloid leukemia on reinduction of BCR-ABL, or imatinib withdrawal. Our results suggest that BCR-ABL induces differentiation of LT-HSCs and decreases their self-renewal capacity.
authors.affiliation: Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany.
authors.forename: Mirle
authors.initials: M
authors.lastname: Schemionek
authors.forename: Christian
authors.initials: C
authors.lastname: Elling
authors.forename: Ulrich
authors.initials: U
authors.lastname: Steidl
authors.forename: Nicole
authors.initials: N
authors.lastname: Bäumer
authors.forename: Ashley
authors.initials: A
authors.lastname: Hamilton
authors.forename: Tilmann
authors.initials: T
authors.lastname: Spieker
authors.forename: Joachim R
authors.initials: JR
authors.lastname: Göthert
authors.forename: Martin
authors.initials: M
authors.lastname: Stehling
authors.forename: Amy
authors.initials: A
authors.lastname: Wagers
authors.forename: Claudia S
authors.initials: CS
authors.lastname: Huettner
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Lara
authors.initials: L
authors.lastname: Tickenbrock
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Berdel
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Tessa L
authors.initials: TL
authors.lastname: Holyoake
authors.forename: Carsten
authors.initials: C
authors.lastname: Müller-Tidow
authors.forename: Steffen
authors.initials: S
authors.lastname: Koschmieder
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002469:Cell Separation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D016313:Genes, abl / Q000502:physiology; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009367:Neoplasm Staging; D009368:Neoplasm Transplantation; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016044:Fusion Proteins, bcr-abl