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Diverging fates of cells of origin in acute and chronic leukaemia.

Kovacic B, Hoelbl A, Litos G, Alacakaptan M, Schuster C, Fischhuber KM, Kerenyi MA, Stengl G, Moriggl R, Sexl V, Beug H - EMBO Mol Med (2012)

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.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Molecular Pathology (I.M.P.), Vienna, Austria. boris.kovacic@vetmeduni.ac.at

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Hierarchy among CML and B-ALL is established by differentiation into classical haematopoietic lineagesIn the ‘continuous supply model’, the cells of origin confer their self-renewal capacity to their descendants. The choice of lineage is oncogene-specific. In the ‘differentiation-driven model’, the cells of origin are pre-leukaemic. Full transformation and self-renewal is achieved after subsequent differentiation at a specific cell stage.BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to LT-HSCs are indicated. One representative FACS plot from each analysed group is depicted (see also Supporting Information Fig S2).BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to CLMPs are indicated. One representative FACS plot from each analysed group is depicted.Transformation of LT-HSCs with either empty vector, BCR/ABLp210 or BCR/ABLp185, followed by in vitro cultivation with SCF, IL-3, IL-6 and IL-7. Contour-plots indicate differentiation into myeloid and lymphoid lineages (left and middle panels) and presence of HSCs (right panel) after 11 days. Numbers indicate percentages of total cells. One representative set of data is depicted (n = 3).Outgrowing cells from BCR/ABLp185-transduced LT-HSCs on day 30 at same conditions as in (D).
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fig02: Hierarchy among CML and B-ALL is established by differentiation into classical haematopoietic lineagesIn the ‘continuous supply model’, the cells of origin confer their self-renewal capacity to their descendants. The choice of lineage is oncogene-specific. In the ‘differentiation-driven model’, the cells of origin are pre-leukaemic. Full transformation and self-renewal is achieved after subsequent differentiation at a specific cell stage.BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to LT-HSCs are indicated. One representative FACS plot from each analysed group is depicted (see also Supporting Information Fig S2).BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to CLMPs are indicated. One representative FACS plot from each analysed group is depicted.Transformation of LT-HSCs with either empty vector, BCR/ABLp210 or BCR/ABLp185, followed by in vitro cultivation with SCF, IL-3, IL-6 and IL-7. Contour-plots indicate differentiation into myeloid and lymphoid lineages (left and middle panels) and presence of HSCs (right panel) after 11 days. Numbers indicate percentages of total cells. One representative set of data is depicted (n = 3).Outgrowing cells from BCR/ABLp185-transduced LT-HSCs on day 30 at same conditions as in (D).

Mentions: One may envision different scenarios underlying the divergent fates of BCR/ABLp185+ and BCR/ABLp210+ LT-HSCs: First, the transformed LT-HSCs may constantly self-renew and supply the leukaemic cell pool in the periphery. Alternatively, the transformed LT-HSCs may represent a pre-leukaemic stage and self-renewal occurs after differentiation into a more mature stage (see scheme in Fig 2A). Thus, we analysed the abundance of GFP+ LT-HSCs in BM from moribund mice originally transplanted with either BCR/ABLp185- or BCR/ABLp210-infected LT-HSCs. We hardly detected GFP+ cells within the HSC-subpopulations in BCR/ABLp185-transplanted mice (Fig 2B, and Supporting Information Fig S2A and B, n = 3). In contrast, GFP+ cells were readily detectable in all HSC-subpopulations of BCR/ABLp210-transplanted mice (69.1 ± 5.7% GFP+ cells within LT-HSCs, Fig 2B; 78.4 ± 8.4% in ST-HSCs and 29 ± 12.3% in MPPs, Supporting Information Fig S2A). The total numbers of HSCs were ∼20 fold increased (Supporting Information Fig S2B, n = 3). Notably, we also detected few BCR/ABLp185+ cells within the CLMP population, (Fig 2C). In contrast, the vast majority of BCR/ABLp210+ CLMPs were GFP+ (Fig 2C). Taken together, these data suggest that mature CML is continuously supplied by the COCs, whereas the initial B-ALL COC-population is lost in case of B-ALL.


Diverging fates of cells of origin in acute and chronic leukaemia.

Kovacic B, Hoelbl A, Litos G, Alacakaptan M, Schuster C, Fischhuber KM, Kerenyi MA, Stengl G, Moriggl R, Sexl V, Beug H - EMBO Mol Med (2012)

Hierarchy among CML and B-ALL is established by differentiation into classical haematopoietic lineagesIn the ‘continuous supply model’, the cells of origin confer their self-renewal capacity to their descendants. The choice of lineage is oncogene-specific. In the ‘differentiation-driven model’, the cells of origin are pre-leukaemic. Full transformation and self-renewal is achieved after subsequent differentiation at a specific cell stage.BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to LT-HSCs are indicated. One representative FACS plot from each analysed group is depicted (see also Supporting Information Fig S2).BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to CLMPs are indicated. One representative FACS plot from each analysed group is depicted.Transformation of LT-HSCs with either empty vector, BCR/ABLp210 or BCR/ABLp185, followed by in vitro cultivation with SCF, IL-3, IL-6 and IL-7. Contour-plots indicate differentiation into myeloid and lymphoid lineages (left and middle panels) and presence of HSCs (right panel) after 11 days. Numbers indicate percentages of total cells. One representative set of data is depicted (n = 3).Outgrowing cells from BCR/ABLp185-transduced LT-HSCs on day 30 at same conditions as in (D).
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Related In: Results  -  Collection

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fig02: Hierarchy among CML and B-ALL is established by differentiation into classical haematopoietic lineagesIn the ‘continuous supply model’, the cells of origin confer their self-renewal capacity to their descendants. The choice of lineage is oncogene-specific. In the ‘differentiation-driven model’, the cells of origin are pre-leukaemic. Full transformation and self-renewal is achieved after subsequent differentiation at a specific cell stage.BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to LT-HSCs are indicated. One representative FACS plot from each analysed group is depicted (see also Supporting Information Fig S2).BM analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and empty vector-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to CLMPs are indicated. One representative FACS plot from each analysed group is depicted.Transformation of LT-HSCs with either empty vector, BCR/ABLp210 or BCR/ABLp185, followed by in vitro cultivation with SCF, IL-3, IL-6 and IL-7. Contour-plots indicate differentiation into myeloid and lymphoid lineages (left and middle panels) and presence of HSCs (right panel) after 11 days. Numbers indicate percentages of total cells. One representative set of data is depicted (n = 3).Outgrowing cells from BCR/ABLp185-transduced LT-HSCs on day 30 at same conditions as in (D).
Mentions: One may envision different scenarios underlying the divergent fates of BCR/ABLp185+ and BCR/ABLp210+ LT-HSCs: First, the transformed LT-HSCs may constantly self-renew and supply the leukaemic cell pool in the periphery. Alternatively, the transformed LT-HSCs may represent a pre-leukaemic stage and self-renewal occurs after differentiation into a more mature stage (see scheme in Fig 2A). Thus, we analysed the abundance of GFP+ LT-HSCs in BM from moribund mice originally transplanted with either BCR/ABLp185- or BCR/ABLp210-infected LT-HSCs. We hardly detected GFP+ cells within the HSC-subpopulations in BCR/ABLp185-transplanted mice (Fig 2B, and Supporting Information Fig S2A and B, n = 3). In contrast, GFP+ cells were readily detectable in all HSC-subpopulations of BCR/ABLp210-transplanted mice (69.1 ± 5.7% GFP+ cells within LT-HSCs, Fig 2B; 78.4 ± 8.4% in ST-HSCs and 29 ± 12.3% in MPPs, Supporting Information Fig S2A). The total numbers of HSCs were ∼20 fold increased (Supporting Information Fig S2B, n = 3). Notably, we also detected few BCR/ABLp185+ cells within the CLMP population, (Fig 2C). In contrast, the vast majority of BCR/ABLp210+ CLMPs were GFP+ (Fig 2C). Taken together, these data suggest that mature CML is continuously supplied by the COCs, whereas the initial B-ALL COC-population is lost in case of B-ALL.

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.

View Article: PubMed Central - PubMed

Affiliation: Research Institute of Molecular Pathology (I.M.P.), Vienna, Austria. boris.kovacic@vetmeduni.ac.at

Show MeSH
Related in: MedlinePlus