BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells.
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.
Schemionek
Mirle
M
Department of Medicine, Hematology and Oncology, University of Münster, Münster, Germany.
Elling
Christian
C
Steidl
Ulrich
U
Bäumer
Nicole
N
Hamilton
Ashley
A
Spieker
Tilmann
T
Göthert
Joachim R
JR
Stehling
Martin
M
Wagers
Amy
A
Huettner
Claudia S
CS
Tenen
Daniel G
DG
Tickenbrock
Lara
L
Berdel
Wolfgang E
WE
Serve
Hubert
H
Holyoake
Tessa L
TL
Müller-Tidow
Carsten
C
Koschmieder
Steffen
S
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
D016044:Fusion Proteins, bcr-abl