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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.

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

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LT-HSCs are cells of origin in BCR/ABLp210 and BCR/ABLp185 leukaemiaA. Whole BM cells and FACS-purified subpopulations were transduced with retroviruses encoding BCR/ABLp210-IRES-GFP, BCR/ABLp185-IRES-GFP or an empty-GFP-vector. Oncogene-infected LT-HSCs—but none of the more mature populations—are able to induce leukaemia with equal frequencies as whole BM cells (see also Supporting Information Fig S1 and Supporting Information Table SI).B. Peripheral blood analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and control vector-transducted LT-HSCs. Relative contribution of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage is indicated. One representative FACS plot from each group is depicted.C, D. Comparison of relative gene expression of lineage-specific TFs in indicated cell fractions purified from wildtype and moribund BCR/ABLp210+ mice (C) and wildtype and moribund BCR/ABLp185+ mice (D). Data show fold differences compared to an internal control (Ube2d2) and are normalized to the gene expression in wildtype HSCs.
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fig01: LT-HSCs are cells of origin in BCR/ABLp210 and BCR/ABLp185 leukaemiaA. Whole BM cells and FACS-purified subpopulations were transduced with retroviruses encoding BCR/ABLp210-IRES-GFP, BCR/ABLp185-IRES-GFP or an empty-GFP-vector. Oncogene-infected LT-HSCs—but none of the more mature populations—are able to induce leukaemia with equal frequencies as whole BM cells (see also Supporting Information Fig S1 and Supporting Information Table SI).B. Peripheral blood analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and control vector-transducted LT-HSCs. Relative contribution of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage is indicated. One representative FACS plot from each group is depicted.C, D. Comparison of relative gene expression of lineage-specific TFs in indicated cell fractions purified from wildtype and moribund BCR/ABLp210+ mice (C) and wildtype and moribund BCR/ABLp185+ mice (D). Data show fold differences compared to an internal control (Ube2d2) and are normalized to the gene expression in wildtype HSCs.

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.


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)

LT-HSCs are cells of origin in BCR/ABLp210 and BCR/ABLp185 leukaemiaA. Whole BM cells and FACS-purified subpopulations were transduced with retroviruses encoding BCR/ABLp210-IRES-GFP, BCR/ABLp185-IRES-GFP or an empty-GFP-vector. Oncogene-infected LT-HSCs—but none of the more mature populations—are able to induce leukaemia with equal frequencies as whole BM cells (see also Supporting Information Fig S1 and Supporting Information Table SI).B. Peripheral blood analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and control vector-transducted LT-HSCs. Relative contribution of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage is indicated. One representative FACS plot from each group is depicted.C, D. Comparison of relative gene expression of lineage-specific TFs in indicated cell fractions purified from wildtype and moribund BCR/ABLp210+ mice (C) and wildtype and moribund BCR/ABLp185+ mice (D). Data show fold differences compared to an internal control (Ube2d2) and are normalized to the gene expression in wildtype HSCs.
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fig01: LT-HSCs are cells of origin in BCR/ABLp210 and BCR/ABLp185 leukaemiaA. Whole BM cells and FACS-purified subpopulations were transduced with retroviruses encoding BCR/ABLp210-IRES-GFP, BCR/ABLp185-IRES-GFP or an empty-GFP-vector. Oncogene-infected LT-HSCs—but none of the more mature populations—are able to induce leukaemia with equal frequencies as whole BM cells (see also Supporting Information Fig S1 and Supporting Information Table SI).B. Peripheral blood analysis of mice transplanted with BCR/ABLp210-, BCR/ABLp185- and control vector-transducted LT-HSCs. Relative contribution of leukaemic (GFP+) cells to the myeloid, lymphoid and erythroid lineage is indicated. One representative FACS plot from each group is depicted.C, D. Comparison of relative gene expression of lineage-specific TFs in indicated cell fractions purified from wildtype and moribund BCR/ABLp210+ mice (C) and wildtype and moribund BCR/ABLp185+ mice (D). Data show fold differences compared to an internal control (Ube2d2) and are normalized to the gene expression in wildtype HSCs.
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.

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