BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells

M Schemionek, C Elling, U Steidl… - Blood, The Journal …, 2010 - ashpublications.org
M Schemionek, C Elling, U Steidl, N Bäumer, A Hamilton, T Spieker, JR Göthert, M Stehling…
Blood, The Journal of the American Society of Hematology, 2010ashpublications.org
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 …
Abstract
In a previously developed inducible transgenic mouse model of chronic myeloid leukemia, we now demonstrate that the disease is transplantable using BCR-ABL+ LinSca-1+c-kit+ (LSK) cells. Interestingly, the phenotype is more severe when unfractionated bone marrow cells are transplanted, yet neither progenitor cells (LinSca-1c-kit+), nor mature granulocytes (CD11b+Gr-1+), nor potential stem cell niche cells (CD45Ter119) 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.
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