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Haematological Malignancies Stem Cells in Acute Lymphoblastic Leukaemia Alex Elder, 1 Olaf Heidenreich 2 and Josef Vormoor 3 1. Postdoctoral Fellow, Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University; 2. Professor of Molecular Haematopoiesis, Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University; 3. Sir James Spence Professor of Child Health, Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, and Honorary Consultant Paediatric Oncologist, Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Abstract There has been significant debate over the identity of cancer stem cell populations in acute lymphoblastic leukaemia (ALL), with different groups reporting seemingly contradictory results. The latest findings suggest that tumour-propagating capacity is found within a high percentage of ALL blasts and that these cells have diverse immunophenotypes, which suggests that ALL follows a stochastic cancer stem cell model – as opposed to a hierarchical model. Recent data add a layer of complexity to the tumour evolution process by showing that the leukaemia-propagating compartment consists of multiple genetically diverse subclones related by Darwinian-style evolutionary trees. Differences in the cell of origin may also affect tumour development. In this article, we discuss the applicability of cancer stem cell models to ALL in the context of these recent findings. Keywords Cancer stem cells, acute lymphoblastic leukaemia, clonal evolution, cell of origin Disclosure: The authors have no conflicts of interest to declare. Received: 2 May 2012 Accepted: 23 July 2012 Citation: European Oncology & Haematology, 2012;8(3):196–200 Correspondence: Josef Vormoor, Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute, 4th floor, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK. E: h.j.vormoor@ncl.ac.uk In the early 1990s, pioneering work from John Dick’s laboratory demonstrated that only a rare subset of malignant acute myeloid leukaemia (AML) cells could reconstitute the disease following successive xenotransplantations in mice. 1 This work was possible due to critical advances in haematopoietic stem cell (HSC) isolation based on surface marker expression profiles, 2 and provided the first experimental evidence for a concept that had been previously discussed for decades: the cancer stem cell (CSC). The CSC model contends that long-term tumour growth is driven by a population of cells with stem cell-like properties, resulting in the formation of tumours that are functionally and morphologically heterogeneous. This heterogeneity can be explained by two CSC models. In the hierarchical model, CSCs are a biologically distinct subset of cells that both sustain the stem cell pool through self-renewal and give rise to progeny lacking extensive proliferative capacity. This model is analogous to the function of stem cells in normal tissue development. It follows from this that elimination of the CSC compartment will result in cessation of tumour growth. In contrast, the stochastic model contends that all cells within a tumour have the potential to act as CSCs and that functional heterogeneity is influenced by other factors. These could be either intrinsic (e.g., varying levels of particular transcription factors) or extrinsic (e.g., the tumour niche). There is a substantial amount of evidence that the hierarchical model applies in some tumours. The initial findings of John Dick’s laboratory, which have since been expanded upon, 3 showed that the long-term tumour-maintaining capacity in AML lies only within a rare 196 subpopulation. Although other studies suggest the phenotype of these cells may be more diverse than initially thought, 4,5 the bulk of the evidence indicates that AML follows a hierarchical stem cell model. Xenotransplantation studies have also demonstrated that other solid tumours follow the hierarchical model, including breast, 6 colon 7,8 and brain 9 cancers. However, it appears that the model may not apply to all tumours, as the frequency of propagating cells in melanoma is very high (one in four) 10 and stem cell activity is associated with all cellular phenotypes 11 – although contradictory findings have been reported. 12 Cancer Stem Cells in Acute Lymphoblastic Leukaemia Acute lymphoblastic leukaemia (ALL) is a malignant disorder of lymphoid progenitor cells and the most common paediatric cancer. It is usually characterised by chromosomal translocations resulting in the formation of oncogenic fusion genes, which cooperate with other oncogenic mutations to induce leukaemia. Common examples include TEL/AML1 (also known as ETV6/RUNX1), BCR/ABL1 (Philadelphia chromosome [Ph+]) and MLL/AF4. 13 Unlike in AML, where a hierarchical CSC model seems to apply, the question of which CSC model describes ALL has remained controversial. Attempts to investigate the issue have used transplantation of ALL cells into immunodeficient mice, a model pioneered by Kamel-Reid et al. in mice with severe combined immunodeficiency (SCID). 14 Initial findings appeared to show that the hierarchical model described the biology of childhood ALL, with only © TOUCH BRIEFINGS 2012