Diverging fates of cells of origin in acute and chronic leukaemia.
The large difference in phenotypes among tumour populations may stem from the stochastic origin of tumours from distinct cells - tumour cells are assumed to retain the phenotypes of the cells from which they derive. Yet, functional studies addressing the cellular origin of leukaemia are lacking. Here we show that the cells of origin of both, BCR/ABL-induced chronic myeloid (CML) and B-cell acute lymphoid leukaemia (B-ALL), resemble long-term haematopoietic stem cells (LT-HSCs). During disease-maintenance, CML LT-HSCs persist to function as cancer stem cells (CSCs) that maintain leukaemia and require signalling by the transcription factor STAT5. In contrast, B-ALL LT-HSCs differentiate into CSCs that correspond to pro-B cells. This transition step requires a transient IL-7 signal and is lost in IL-7Rα-deficient cells. Thus, in BCR/ABLp185(+)  B-ALL and BCR/ABLp210(+)  CML, the final phenotype of the tumour as well as the abundance of CSCs is dictated by diverging differentiation fates of their common cells of origin.
Research Institute of Molecular Pathology (I.M.P.), Vienna, Austria. boris.kovacic@vetmeduni.ac.at
Boris
B
Kovacic
Andrea
A
Hoelbl
Gabriele
G
Litos
Memetcan
M
Alacakaptan
Christian
C
Schuster
Katrin M
KM
Fischhuber
Marc A
MA
Kerenyi
Gabriele
G
Stengl
Richard
R
Moriggl
Veronika
V
Sexl
Hartmut
H
Beug
D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D006801:Humans; D015471:Leukemia, Basophilic, Acute / Q000378:metabolism / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D050799:STAT5 Transcription Factor / Q000378:metabolism
D050799:STAT5 Transcription Factor