Diverging fates of cells of origin in acute and chronic leukaemia.
Bottom Line: 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.
Affiliation: Research Institute of Molecular Pathology (I.M.P.), Vienna, Austria. firstname.lastname@example.orgShow MeSH
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Mentions: To discover the COC of CML and B-ALL, we isolated (i) unfractionated bone marrow (BM) cells, (ii) purified long-term haematopoietic stem cells (LT-HSCs), (iii) purified common lympho-myeloid progenitors (CLMPs) and (iv) purified HSC-depleted BM, from wildtype mice (see Supporting Information Fig S1A and B, and Supporting Information Table SI). The obtained cell populations were retrovirally transduced with either BCR/ABLp210-IRES-GFP, or BCR/ABLp185-IRES-GFP or a control vector (empty-IRES-GFP) and injected into lethally irradiated syngeneic wildtype mice. The disease induced by transduction of BCR/ABLp210 into unfractionated BM cells resembled CML (n = 9 in total), whereas BCR/ABLp185-transduced BM cells conferred a B-ALL (n = 6 in total; Fig 1A, Supporting Information Fig S1C and D). Strikingly, only the infection of purified LT-HSCs with BCR/ABLp210 or BCR/ABLp185 induced CML or B-ALL in all mice, respectively (Fig 1A, n = 4 each). Neither the infection of purified CLMPs (n = 4 and n = 5, respectively) nor the HSC-depleted BM (n = 5 and n = 4, respectively) resulted in leukaemia formation (Fig 1A). The disease incidence and the properties of leukaemia inflicted by the respective oncogenes were similar, regardless whether whole BM or LT-HSCs were infected. This led us to conclude that LT-HSCs represent the COCs of leukaemia induced by both fusion-oncogenes.
Affiliation: Research Institute of Molecular Pathology (I.M.P.), Vienna, Austria. email@example.com