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Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations.

Rehe K, Wilson K, Bomken S, Williamson D, Irving J, den Boer ML, Staa M, Schrappe M, Hall AG, Heidenreich O, Vormoor J - EMBO Mol Med (2012)

Bottom Line: Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34.The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations.Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

View Article: PubMed Central - PubMed

Affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

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Related in: MedlinePlus

Models for regulation of self-renewal, proliferation and differentiation in normal haematopoietic stem cells and acute myeloid leukaemia as compared with acute lymphoblastic leukaemiaIn normal haematopoietic stem cells and AML, self-renewal is tightly regulated by a differentiation-dependent loss of self-renewal.In B-ALL, clonal expansion is tightly regulated by the dependence of positive survival and proliferation signals. Without those lymphoid blasts undergo apoptosis.
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fig05: Models for regulation of self-renewal, proliferation and differentiation in normal haematopoietic stem cells and acute myeloid leukaemia as compared with acute lymphoblastic leukaemiaIn normal haematopoietic stem cells and AML, self-renewal is tightly regulated by a differentiation-dependent loss of self-renewal.In B-ALL, clonal expansion is tightly regulated by the dependence of positive survival and proliferation signals. Without those lymphoid blasts undergo apoptosis.

Mentions: Our xenotransplantation data suggested that blasts sorted for different surface markers should express key components of cellular programmes that are essential for a high, if not unlimited, proliferative potential. The candidate gene we chose to test this hypothesis was TERT, which controls self-renewal of normal and cancer stem cells, and whose expression is maintained by key leukaemic fusion oncogenes supporting its essential role in leukaemic propagation (Gessner et al, 2010). As predicted, quantitative RT-PCR analysis revealed that there were no differences in TERT expression between CD34high and CD34low leukaemic blasts. This is similar to normal B-cell development: in line with the high proliferative potential, lymphocytes are the only cellular compartment in humans in which TERT expression is maintained even during the late stages of differentiation and can be up-regulated with activation and proliferation (Liu et al, 1999; Lobetti-Bodoni et al, 2010; Son et al, 2003). Notably, none of gene expression signatures generated from AML or normal cells with self-renewal potential (Eppert et al, 2011; Gentles et al, 2010; Kim et al, 2009) distinguished CD34high from CD34low blasts in B-ALL, indicating their similarity in relation to expression of candidate stem cell genes. These expression data are consistent with our model that, unlike the myeloid lineage, B-ALL shows no dissociation between self-renewal and differentiation (Fig 5). Notably, one of the early pioneers of stem cell biology, the late Dr Ernest McCulloch, stated that ‘a minimum conclusion to be reached from the comparison of myelopoiesis and lymphopoiesis is that a firm linkage between differentiation and loss of proliferative capacity is not a general characteristic of hemopoiesis’ (McCulloch, 1983). Normal mature lymphoid cells maintain their ability to clonally expand—a characteristic, which is a core element of the lymphocyte response to re-exposure to antigen. Lymphoid cells can therefore be considered unipotent stem cells and we show here that this may also apply to malignant blasts in B lineage acute leukaemia.


Acute B lymphoblastic leukaemia-propagating cells are present at high frequency in diverse lymphoblast populations.

Rehe K, Wilson K, Bomken S, Williamson D, Irving J, den Boer ML, Staa M, Schrappe M, Hall AG, Heidenreich O, Vormoor J - EMBO Mol Med (2012)

Models for regulation of self-renewal, proliferation and differentiation in normal haematopoietic stem cells and acute myeloid leukaemia as compared with acute lymphoblastic leukaemiaIn normal haematopoietic stem cells and AML, self-renewal is tightly regulated by a differentiation-dependent loss of self-renewal.In B-ALL, clonal expansion is tightly regulated by the dependence of positive survival and proliferation signals. Without those lymphoid blasts undergo apoptosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569652&req=5

fig05: Models for regulation of self-renewal, proliferation and differentiation in normal haematopoietic stem cells and acute myeloid leukaemia as compared with acute lymphoblastic leukaemiaIn normal haematopoietic stem cells and AML, self-renewal is tightly regulated by a differentiation-dependent loss of self-renewal.In B-ALL, clonal expansion is tightly regulated by the dependence of positive survival and proliferation signals. Without those lymphoid blasts undergo apoptosis.
Mentions: Our xenotransplantation data suggested that blasts sorted for different surface markers should express key components of cellular programmes that are essential for a high, if not unlimited, proliferative potential. The candidate gene we chose to test this hypothesis was TERT, which controls self-renewal of normal and cancer stem cells, and whose expression is maintained by key leukaemic fusion oncogenes supporting its essential role in leukaemic propagation (Gessner et al, 2010). As predicted, quantitative RT-PCR analysis revealed that there were no differences in TERT expression between CD34high and CD34low leukaemic blasts. This is similar to normal B-cell development: in line with the high proliferative potential, lymphocytes are the only cellular compartment in humans in which TERT expression is maintained even during the late stages of differentiation and can be up-regulated with activation and proliferation (Liu et al, 1999; Lobetti-Bodoni et al, 2010; Son et al, 2003). Notably, none of gene expression signatures generated from AML or normal cells with self-renewal potential (Eppert et al, 2011; Gentles et al, 2010; Kim et al, 2009) distinguished CD34high from CD34low blasts in B-ALL, indicating their similarity in relation to expression of candidate stem cell genes. These expression data are consistent with our model that, unlike the myeloid lineage, B-ALL shows no dissociation between self-renewal and differentiation (Fig 5). Notably, one of the early pioneers of stem cell biology, the late Dr Ernest McCulloch, stated that ‘a minimum conclusion to be reached from the comparison of myelopoiesis and lymphopoiesis is that a firm linkage between differentiation and loss of proliferative capacity is not a general characteristic of hemopoiesis’ (McCulloch, 1983). Normal mature lymphoid cells maintain their ability to clonally expand—a characteristic, which is a core element of the lymphocyte response to re-exposure to antigen. Lymphoid cells can therefore be considered unipotent stem cells and we show here that this may also apply to malignant blasts in B lineage acute leukaemia.

Bottom Line: Here, we demonstrate in a wide range of primary patient samples and patient samples previously passaged through mice that leukaemia-propagating cells are found in all populations defined by high or low expression of the lymphoid differentiation markers CD10, CD20 or CD34.The frequency of leukaemia-propagating cells and their engraftment kinetics do not differ between these populations.Together, these findings suggest that there is no stem cell hierarchy in acute B lymphoblastic leukaemia.

View Article: PubMed Central - PubMed

Affiliation: Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.

Show MeSH
Related in: MedlinePlus