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

Schemionek, M. et al. (2010) BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. Blood, 115(16), pp. 3185-3195. (doi: 10.1182/blood-2009-04-215376)

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Publisher's URL: http://dx.doi.org/10.1182/blood-2009-04-215376

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

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Holyoake, Professor Tessa and Hamilton, Ms Ashley
Authors: Schemionek, M., Elling, C., Steidl, U., Baumer, N., Hamilton, A., Spieker, T., Gothert, J. R., Stehling, M., Wagers, A., Huettner, C. S., Tenen, D. G., Tickenbrock, L., Berdel, W. E., Serve, H., Holyoake, T. L., Muller-Tidow, C., and Koschmieder, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Blood
Publisher:American Society of Hematology
ISSN:0006-4971
ISSN (Online):1528-0020
Published Online:06 January 2010
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