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

Mirle Schemionek, Christian Elling, Ulrich G. 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 Citations (Scopus)

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

Fingerprint

Hematopoietic Stem Cells
Stem cells
Stem Cells
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phenotype
Bone
Stem Cell Niche
Granulocytes
Bone Marrow Cells
Transgenic Mice
Genes
Transplantation
Bone Marrow
Cells
Gene Expression
Imatinib Mesylate

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Schemionek, M., Elling, C., Steidl, U. G., Bäumer, N., Hamilton, A., Spieker, T., ... 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

BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. / Schemionek, Mirle; Elling, Christian; Steidl, Ulrich G.; Bäumer, Nicole; Hamilton, Ashley; Spieker, Tilmann; Göthert, Joachim R.; Stehling, Martin; Wagers, Amy; Huettner, Claudia S.; Tenen, Daniel G.; Tickenbrock, Lara; Berdel, Wolfgang E.; Serve, Hubert; Holyoake, Tessa L.; Müller-Tidow, Carsten; Koschmieder, Steffen.

In: Blood, Vol. 115, No. 16, 22.04.2010, p. 3185-3195.

Research output: Contribution to journalArticle

Schemionek, M, Elling, C, Steidl, UG, Bäumer, N, Hamilton, A, Spieker, T, Göthert, JR, Stehling, M, Wagers, A, Huettner, CS, Tenen, DG, Tickenbrock, L, Berdel, WE, Serve, H, Holyoake, TL, Müller-Tidow, C & Koschmieder, S 2010, 'BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells', Blood, vol. 115, no. 16, pp. 3185-3195. https://doi.org/10.1182/blood-2009-04-215376
Schemionek M, Elling C, Steidl UG, Bäumer N, Hamilton A, Spieker T et al. BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. Blood. 2010 Apr 22;115(16):3185-3195. https://doi.org/10.1182/blood-2009-04-215376
Schemionek, Mirle ; Elling, Christian ; Steidl, Ulrich G. ; Bäumer, Nicole ; Hamilton, Ashley ; Spieker, Tilmann ; Göthert, Joachim R. ; Stehling, Martin ; Wagers, Amy ; Huettner, Claudia S. ; Tenen, Daniel G. ; Tickenbrock, Lara ; Berdel, Wolfgang E. ; Serve, Hubert ; Holyoake, Tessa L. ; Müller-Tidow, Carsten ; Koschmieder, Steffen. / BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells. In: Blood. 2010 ; Vol. 115, No. 16. pp. 3185-3195.
@article{72e8fa95af124fa7866246e29d2f119f,
title = "BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells",
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.",
author = "Mirle Schemionek and Christian Elling and Steidl, {Ulrich G.} and Nicole B{\"a}umer and Ashley Hamilton and Tilmann Spieker and G{\"o}thert, {Joachim R.} and Martin Stehling and Amy Wagers and Huettner, {Claudia S.} and Tenen, {Daniel G.} and Lara Tickenbrock and Berdel, {Wolfgang E.} and Hubert Serve and Holyoake, {Tessa L.} and Carsten M{\"u}ller-Tidow and Steffen Koschmieder",
year = "2010",
month = "4",
day = "22",
doi = "10.1182/blood-2009-04-215376",
language = "English (US)",
volume = "115",
pages = "3185--3195",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "16",

}

TY - JOUR

T1 - BCR-ABL enhances differentiation of long-term repopulating hematopoietic stem cells

AU - Schemionek, Mirle

AU - Elling, Christian

AU - Steidl, Ulrich G.

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.

UR - http://www.scopus.com/inward/record.url?scp=77951446379&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951446379&partnerID=8YFLogxK

U2 - 10.1182/blood-2009-04-215376

DO - 10.1182/blood-2009-04-215376

M3 - Article

VL - 115

SP - 3185

EP - 3195

JO - Blood

JF - Blood

SN - 0006-4971

IS - 16

ER -