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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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STAT5 is necessary and sufficient for the leukaemogenic activity of cells of origin of CMLWhole BM cells and indicated FACS-purified subpopulations were transduced with retroviruses encoding caSTAT5-IRES-GFP. Infected LT-HSCs were the only population able to induce leukaemia with equal frequencies like whole BM cells (see Supporting Information Fig S5).Peripheral blood analysis of mice transplanted with caSTAT5-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage are indicated. One representative FACS plot from each analysed group is depicted.
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fig04: STAT5 is necessary and sufficient for the leukaemogenic activity of cells of origin of CMLWhole BM cells and indicated FACS-purified subpopulations were transduced with retroviruses encoding caSTAT5-IRES-GFP. Infected LT-HSCs were the only population able to induce leukaemia with equal frequencies like whole BM cells (see Supporting Information Fig S5).Peripheral blood analysis of mice transplanted with caSTAT5-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage are indicated. One representative FACS plot from each analysed group is depicted.

Mentions: STAT5 is a critical node in the signalling network downstream of BCR/ABL (Hoelbl et al, 2006, 2010) and overexpression of a constitutively active STAT5 protein (caSTAT5) in BM cells suffices to induce CML, closely resembling a BCR/ABLp210-induced disease (Moriggl et al, 2005). Hence, STAT5 might act as a relevant factor driving self-renewal of haematopoietic cells. Therefore, we asked whether STAT5 signalling is critical within the LT-HSCs or within more mature progenitors for the initiation of CML. Transformation of whole BM and purified LT-HSCs with caSTAT5, both led to induction of CML in vivo (Fig 4A), whereas the transformation of CLMPs or HSC-depleted BM failed to do so. Upon transplantation of caSTAT5+ LT-HSCs, GFP+ cells were present throughout all haematopoietic lineages and all stages of differentiation, and densely infiltrated BM, spleen and liver (Fig 4B and data not shown). Again, we found augmented numbers of HSCs in the BM of leukaemic mice (Supporting Information Fig S4A), reminiscent to our observations made in BCR/ABLp210 transplants. Furthermore, the vast majority of caSTAT5+ ST-HSCs, MPPs and CLMPs were GFP+ (Supporting Information Fig S4B). These results indicated that STAT5-activation in LT-HSCs is sufficient to initiate a CML-like disease.


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)

STAT5 is necessary and sufficient for the leukaemogenic activity of cells of origin of CMLWhole BM cells and indicated FACS-purified subpopulations were transduced with retroviruses encoding caSTAT5-IRES-GFP. Infected LT-HSCs were the only population able to induce leukaemia with equal frequencies like whole BM cells (see Supporting Information Fig S5).Peripheral blood analysis of mice transplanted with caSTAT5-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage are indicated. One representative FACS plot from each analysed group is depicted.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3376859&req=5

fig04: STAT5 is necessary and sufficient for the leukaemogenic activity of cells of origin of CMLWhole BM cells and indicated FACS-purified subpopulations were transduced with retroviruses encoding caSTAT5-IRES-GFP. Infected LT-HSCs were the only population able to induce leukaemia with equal frequencies like whole BM cells (see Supporting Information Fig S5).Peripheral blood analysis of mice transplanted with caSTAT5-transduced LT-HSCs. Relative contributions of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage are indicated. One representative FACS plot from each analysed group is depicted.
Mentions: STAT5 is a critical node in the signalling network downstream of BCR/ABL (Hoelbl et al, 2006, 2010) and overexpression of a constitutively active STAT5 protein (caSTAT5) in BM cells suffices to induce CML, closely resembling a BCR/ABLp210-induced disease (Moriggl et al, 2005). Hence, STAT5 might act as a relevant factor driving self-renewal of haematopoietic cells. Therefore, we asked whether STAT5 signalling is critical within the LT-HSCs or within more mature progenitors for the initiation of CML. Transformation of whole BM and purified LT-HSCs with caSTAT5, both led to induction of CML in vivo (Fig 4A), whereas the transformation of CLMPs or HSC-depleted BM failed to do so. Upon transplantation of caSTAT5+ LT-HSCs, GFP+ cells were present throughout all haematopoietic lineages and all stages of differentiation, and densely infiltrated BM, spleen and liver (Fig 4B and data not shown). Again, we found augmented numbers of HSCs in the BM of leukaemic mice (Supporting Information Fig S4A), reminiscent to our observations made in BCR/ABLp210 transplants. Furthermore, the vast majority of caSTAT5+ ST-HSCs, MPPs and CLMPs were GFP+ (Supporting Information Fig S4B). These results indicated that STAT5-activation in LT-HSCs is sufficient to initiate a CML-like disease.

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