Right on target: eradicating leukemic stem cells

Less than a third of adults with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. The discovery over a decade ago that myeloid leukemias originate from rare stem-like cells that can transfer the disease to immunodeficient mice suggested that these 'leukemia stem cells' (LSCs) are responsible for relapse of leukemia following conventional or targeted cancer therapy and that eradication of LSCs might be necessary to cure the disease permanently. Several recent studies have provided insight into the signaling pathways underlying the LSC phenotype and have also described approaches to eliminate LSCs with antibodies. Here, we review recent advances in LSC research and discuss novel therapeutic strategies to specifically target LSCs. Less than a third of adults with acute myeloid leukemia (AML) are cured by current treatments, emphasizing the need for new approaches to therapy. The discovery over a decade ago that myeloid leukemias originate from rare stem-like cells that can transfer the disease to immunodeficient mice suggested that these 'leukemia stem cells' (LSCs) are responsible for relapse of leukemia following conventional or targeted cancer therapy and that eradication of LSCs might be necessary to cure the disease permanently. Several recent studies have provided insight into the signaling pathways underlying the LSC phenotype and have also described approaches to eliminate LSCs with antibodies. Here, we review recent advances in LSC research and discuss novel therapeutic strategies to specifically target LSCs. a clonal hematopoietic malignancy characterized by overproduction of immature myeloid cells (blasts) with a block in differentiation. the malignant cell in acute leukemia, characterized by a non-terminally differentiated hematopoietic cell. rare cells present in tumors that are defined functionally by their ability to transfer the malignancy on xenotransplantation into an immunodeficient recipient animal (usually NOD-SCID mice). Synonyms include cancer-initiating cells and tumorigenic cells. this states that tumors are maintained in their host by a small population of stem-like cancer cells that have the capacity for indefinite self-renewal. Cancer must either originate from cells, such as normal tissue stem cells, that already possess the capacity for self-renewal or else self-renewal must be acquired aberrantly during tumorigenesis. defined as the cell in which the first leukemia-specific genetic event, such as a chromosomal translocation or mutation, has occurred. The cell of origin of a leukemia might be different from the leukemic stem cell that is present once the leukemia is established because the phenotype and properties might change during leukemogenesis. a myeloproliferative disease characterized by clonal overproduction of maturing myeloid cells and disease progression towards blast crisis, a condition resembling AML. CML is caused by the product of the Philadelphia chromosome, the BCR–ABL fusion tyrosine kinase. a hematopoietic cell that has the capacity to differentiate into one or more myeloid cell lineages based on colony-forming assays and transplantation but has limited self-renewal capacity. cancer stem cells were first identified in AML and designated as leukemia-initiating cells or leukemia stem cells. evidence for the presence of residual malignant cells, even when so few cancer cells are present that they cannot be detected by histopathology or cytogenetics. Some methods for detecting MRD include flow cytometry and reverse-transcriptase PCR for fusion transcripts. the absence of leukemia-specific fusion transcripts detected by reverse-transcriptase PCR. a group of clonal hematopoietic diseases originating in multipotent hematopoietic stem/progenitor cells that is characterized by overproduction of mature myeloid cells of particular lineages. MPDs include CML (overproduction of neutrophils), polycythemia vera [(PV) overproduction of erythrocytes], essential thrombocythemia [(ET) overproduction of platelets] and primary myelofibrosis (marrow fibrosis with extramedullary hematopoiesis). non-obese diabetic–severe combined immunodeficiency mice. These mice lack mature B and T lymphocytes and functional natural killer cells and will accept hematopoietic cell grafts from humans. self-renewal reflects the ability of a stem cell to divide asymmetrically, yielding one daughter cell that can differentiate and another that maintains pluripotent stem-cell function. For both normal HSCs and LSCs, self-renewal is defined rigorously by serial transplantation, enabling regeneration of cells with the ability for multi-lineage hematopoietic repopulation (for HSCs) or propagation of leukemia (for LSCs). It is distinct from proliferation, which might generate daughter cells that both lack pluripotency. transplantation of human hematopoietic cells into immunodeficient mice (such as NOD–SCID mice).