Leukemia stem cells and human acute lymphoblastic leukemia

Abstract

Leukemias and other cancers have been proposed to contain a subpopulation of cells that display characteristics of stem cells and maintain tumor growth. The fact that most anticancer therapy is directed against the bulk of the tumor, and possibly spares the cancer stem cells, may lie at the heart of treatment failures with conventional modalities. Leukemia stem cells are fairly well described for acute myeloid leukemia (AML), but their existence and relevance for acute lymphoblastic leukemia (ALL) is less clear. Several reports describe subpopulations with primitive phenotypes in clinical ALL samples. However, it has also been suggested that the majority of leukemic subfractions can propagate leukemia in the appropriate experimental setting, and that their hierarchical organization is less strict than in AML. In addition, it is uncertain whether cancer stem cells arise from malignant transformation of a tissue-specific stem cell, or from committed progenitors or differentiated cells that re-acquire a stem cell-like program. In common childhood ALL, current evidence points towards the cell of origin being a committed lymphoid progenitor. In this review, we highlight recent findings relating to the question of leukemia stem cells in ALL.

Fig. 1. Possible cells of origin in different leukemia stem cell models

A. A genetic event occurring in a stem cell leads to malignant transformation. The stem cell possesses (and contributes) the ability to self renew. The leukemic cells continue to develop along the lymphoid lineage and arrest at the pro or pre-B stage. B. A genetic event occurs in a committed progenitor (CLP, pro-B or pre-B cell), leading to a stem cell like genetic program. The leukemia cells develop further and arrest at a pro or pre-B cell stage.

Fig. 2

Schematic demonstrating expression of cell surface antigens that can be used to characterize stages of B-lymphoid differentiation.

Fig. 3. Hierarchy and differentiation in different leukemia stem cell models

Normal Differentiation toward the B-cell lineage is shown. A. Leukemia sustained by a very early leukemia stem cell (similar to a hematopoietic stem cell or very early progenitor). The leukemic cells continue to develop along the lymphoid lineage and arrest at the pre-B stage. B. Leukemia sustained by a leukemia stem cell at the developmental stage of a committed progenitor (here a pro-B cell), with further differentiation of its progeny along the lymphoid lineage, and arrest at the pre-B stage. C. Leukemia maintained by “leukemia stem cells” corresponding to different stages in early B-cell development. Multiple subpopulations possess the ability to self-renew and propagate the leukemia.