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

Mirle Schemionek, Christian Elling, Ulrich Steidl, Nicole Bäumer, Ashley Hamilton, Tilmann Spieker, Joachim R. Göthert, Martin Stehling, Amy Wagers, Claudia S. Huettner, Daniel G. Tenen, Lara Tickenbrock, Wolfgang E. Berdel, Hubert Serve, Tessa L. Holyoake, Carsten Müller-Tidow, Steffen Koschmieder

Research output: Contribution to journalArticle

66 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3185-3195
Number of pages11
JournalBlood
Volume115
Issue number16
DOIs
StatePublished - Apr 22 2010

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Schemionek, M., Elling, C., Steidl, U., Bäumer, N., Hamilton, A., Spieker, T., Göthert, J. R., Stehling, M., Wagers, A., Huettner, C. S., Tenen, D. G., Tickenbrock, L., Berdel, W. E., Serve, H., Holyoake, T. L., Müller-Tidow, C., & Koschmieder, S. (2010). BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. Blood, 115(16), 3185-3195. https://doi.org/10.1182/blood-2009-04-215376