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.