Different subsets of primary chronic myeloid leukemia stem cells engraft immunodeficient mice and produce a model of the human disease.
Xenograft models of chronic phase human chronic myeloid leukemia (CML) have been difficult to develop because of the persistence of normal hematopoietic stem cells in most chronic phase CML patients and the lack of methods to selectively isolate the rarer CML stem cells. To circumvent this problem, we first identified nine patients' samples in which the long-term culture-initiating cells were predominantly leukemic and then transplanted cells from these samples into sublethally irradiated NOD/SCID and NOD/SCID-beta2microglobulin-/- mice. This resulted in the consistent and durable (>5 months) repopulation of both host genotypes with similar numbers of BCR-ABL+/Ph+ cells. The regenerated leukemic cells included an initial, transient population derived from CD34+CD38+ cells as well as more sustained populations derived from CD34+CD38- progenitors, indicative of a hierarchy of transplantable leukemic cells. Analysis of the phenotypes produced revealed a reduced output of B-lineage cells, enhanced myelopoiesis with excessive production of erythroid and megakaropoietic cells and the generation of primitive (CD34+) leukemic cells displaying an autocrine IL-3 and G-CSF phenotype, all characteristics of primary CML cells. These findings demonstrate the validity of this xenograft model of chronic phase human CML, which should enable future investigation of disease pathogenesis and new approaches to therapy.
Eisterer
W
W
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada.
Jiang
X
X
Christ
O
O
Glimm
H
H
Lee
K H
KH
Pang
E
E
Lambie
K
K
Shaw
G
G
Holyoake
T L
TL
Petzer
A L
AL
Auewarakul
C
C
Barnett
M J
MJ
Eaves
C J
CJ
Eaves
A C
AC
D000818:Animals; D004195:Disease Models, Animal; D006085:Graft Survival; D016179:Granulocyte Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D007942:Leukemia, Experimental / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D014411:Neoplastic Stem Cells / Q000637:transplantation*; D010641:Phenotype; D011828:Radiation Chimera; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods
D007377:Interleukin-3; D016179:Granulocyte Colony-Stimulating Factor