TY - JOUR
T1 - BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells
AU - Schemionek, Mirle
AU - Elling, Christian
AU - Steidl, Ulrich
AU - Bäumer, Nicole
AU - Hamilton, Ashley
AU - Spieker, Tilmann
AU - Göthert, Joachim R.
AU - Stehling, Martin
AU - Wagers, Amy
AU - Huettner, Claudia S.
AU - Tenen, Daniel G.
AU - Tickenbrock, Lara
AU - Berdel, Wolfgang E.
AU - Serve, Hubert
AU - Holyoake, Tessa L.
AU - Müller-Tidow, Carsten
AU - Koschmieder, Steffen
PY - 2010/4/22
Y1 - 2010/4/22
N2 - In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCRABL+ 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 BCRABL induces differentiation of LT-HSCs and decreases their self-renewal capacity.
AB - In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCRABL+ 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 BCRABL induces differentiation of LT-HSCs and decreases their self-renewal capacity.
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U2 - 10.1182/blood-2009-04-215376
DO - 10.1182/blood-2009-04-215376
M3 - Article
C2 - 20053753
AN - SCOPUS:77951446379
SN - 0006-4971
VL - 115
SP - 3185
EP - 3195
JO - Blood
JF - Blood
IS - 16
ER -