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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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BCR/ABLp210 and BCR/ABLp185 CSCs are distinct in phenotypeModels for leukaemia-maintenance. In model 1, all leukaemic cells have the ability to re-initiate leukaemia. Model 2 assumes that leukaemia is maintained either by frequent progenitors, lineage-restricted precursor cells or mature cells. In model 3, the leukaemia-maintaining cell is a rare LT-HSC. Predicted experimental outcomes are indicated for each model.CSCs in BCR/ABLp210 leukaemia behave according to model 3. A mixture of BCR/ABLp210 LT-HSCs with wildtype HSC-depleted BM induces a CML-like disease (upper panel) in 9:9 serially transplanted mice. Mixture of wildtype LT-HSCs with frequent, leukaemic BCR/ABLp210 HSC-depleted BM leaves the mice disease-free for 14 months in 12:12 mice (lower panel, see also Supporting Information Fig S4).CSCs in BCR/ABLp185 leukaemia behave according to model 2. The mixture of BCR/ABLp185 LT-HSCs with wildtype HSC-depleted BM prevents B-ALL formation in 4:4 mice (upper panel). Mixture of wildtype LT-HSCs with frequent BCR/ABLp185 HSC-depleted BM induces a B-ALL in 8:8 serially transplanted mice (lower panel).
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fig05: BCR/ABLp210 and BCR/ABLp185 CSCs are distinct in phenotypeModels for leukaemia-maintenance. In model 1, all leukaemic cells have the ability to re-initiate leukaemia. Model 2 assumes that leukaemia is maintained either by frequent progenitors, lineage-restricted precursor cells or mature cells. In model 3, the leukaemia-maintaining cell is a rare LT-HSC. Predicted experimental outcomes are indicated for each model.CSCs in BCR/ABLp210 leukaemia behave according to model 3. A mixture of BCR/ABLp210 LT-HSCs with wildtype HSC-depleted BM induces a CML-like disease (upper panel) in 9:9 serially transplanted mice. Mixture of wildtype LT-HSCs with frequent, leukaemic BCR/ABLp210 HSC-depleted BM leaves the mice disease-free for 14 months in 12:12 mice (lower panel, see also Supporting Information Fig S4).CSCs in BCR/ABLp185 leukaemia behave according to model 2. The mixture of BCR/ABLp185 LT-HSCs with wildtype HSC-depleted BM prevents B-ALL formation in 4:4 mice (upper panel). Mixture of wildtype LT-HSCs with frequent BCR/ABLp185 HSC-depleted BM induces a B-ALL in 8:8 serially transplanted mice (lower panel).

Mentions: In contrast to the CSC model, the stochastic model does not discriminate between pseudo-hierarchical tumours (Quintana et al, 2010) and non-hierarchical tumours (Williams et al, 2007). Hence, we devised three hypothetical scenarios how BCR/ABLp210 CML and BCR/ABLp185 B-ALL progress based on the phenotypical characterization and hierarchical structure of the haematopoietic system (Fig 5A). In the first model, all leukaemic cells are capable to maintain leukaemia irrespective of their phenotype. The second model assumes that only one subtype of phenotypically defined cells act as a CSC. In the third model, rare HSC-like cells exclusively function as CSCs.


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)

BCR/ABLp210 and BCR/ABLp185 CSCs are distinct in phenotypeModels for leukaemia-maintenance. In model 1, all leukaemic cells have the ability to re-initiate leukaemia. Model 2 assumes that leukaemia is maintained either by frequent progenitors, lineage-restricted precursor cells or mature cells. In model 3, the leukaemia-maintaining cell is a rare LT-HSC. Predicted experimental outcomes are indicated for each model.CSCs in BCR/ABLp210 leukaemia behave according to model 3. A mixture of BCR/ABLp210 LT-HSCs with wildtype HSC-depleted BM induces a CML-like disease (upper panel) in 9:9 serially transplanted mice. Mixture of wildtype LT-HSCs with frequent, leukaemic BCR/ABLp210 HSC-depleted BM leaves the mice disease-free for 14 months in 12:12 mice (lower panel, see also Supporting Information Fig S4).CSCs in BCR/ABLp185 leukaemia behave according to model 2. The mixture of BCR/ABLp185 LT-HSCs with wildtype HSC-depleted BM prevents B-ALL formation in 4:4 mice (upper panel). Mixture of wildtype LT-HSCs with frequent BCR/ABLp185 HSC-depleted BM induces a B-ALL in 8:8 serially transplanted mice (lower panel).
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getmorefigures.php?uid=PMC3376859&req=5

fig05: BCR/ABLp210 and BCR/ABLp185 CSCs are distinct in phenotypeModels for leukaemia-maintenance. In model 1, all leukaemic cells have the ability to re-initiate leukaemia. Model 2 assumes that leukaemia is maintained either by frequent progenitors, lineage-restricted precursor cells or mature cells. In model 3, the leukaemia-maintaining cell is a rare LT-HSC. Predicted experimental outcomes are indicated for each model.CSCs in BCR/ABLp210 leukaemia behave according to model 3. A mixture of BCR/ABLp210 LT-HSCs with wildtype HSC-depleted BM induces a CML-like disease (upper panel) in 9:9 serially transplanted mice. Mixture of wildtype LT-HSCs with frequent, leukaemic BCR/ABLp210 HSC-depleted BM leaves the mice disease-free for 14 months in 12:12 mice (lower panel, see also Supporting Information Fig S4).CSCs in BCR/ABLp185 leukaemia behave according to model 2. The mixture of BCR/ABLp185 LT-HSCs with wildtype HSC-depleted BM prevents B-ALL formation in 4:4 mice (upper panel). Mixture of wildtype LT-HSCs with frequent BCR/ABLp185 HSC-depleted BM induces a B-ALL in 8:8 serially transplanted mice (lower panel).
Mentions: In contrast to the CSC model, the stochastic model does not discriminate between pseudo-hierarchical tumours (Quintana et al, 2010) and non-hierarchical tumours (Williams et al, 2007). Hence, we devised three hypothetical scenarios how BCR/ABLp210 CML and BCR/ABLp185 B-ALL progress based on the phenotypical characterization and hierarchical structure of the haematopoietic system (Fig 5A). In the first model, all leukaemic cells are capable to maintain leukaemia irrespective of their phenotype. The second model assumes that only one subtype of phenotypically defined cells act as a CSC. In the third model, rare HSC-like cells exclusively function as CSCs.

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