Acute Myeloid Leukemia Stem Cells: Seek and Destroy
Acute Myeloid Leukemia Stem Cells: Seek and Destroy
Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are frequent even after aggressive multiagent chemotherapy and allogeneic stem cell transplantation. AML is a biologically heterogeneous disease, characterized by frequent cytogenetic abnormalities and an increasing spectrum of genetic mutations and molecular aberrations. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation. These cells may persist after treatment and are probably responsible for disease relapse. This review will describe bench and translational research in LSCs and discuss how the data should be used to change the direction of developmental therapeutics and clinical trials in AML.
Most adult patients with acute myeloid leukemia (AML) die from their disease despite achieving initial complete remission (CR), including those treated with aggressive multiagent chemotherapy and allogeneic stem cell transplantation. Numerous Phase I, II and III clinical trials of both novel and conventional agents have failed to improve overall survival for older patients and the 5-year survival for younger patients is still only approximately 40%. Thus, it is obvious in the clinic that certain leukemic cells must be fundamentally resistant to our currently available armamentarium of chemotherapy, immunotherapy and radiation. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation into malignant blasts. At least some of these cells persist after treatment and are probably responsible for disease relapse. Clinical data show that for patients in morphologic CR, the presence of minimal residual disease (MRD), as detected by sensitive flow cytometric assays, predicts for disease relapse in AML. Furthermore, a high stem cell frequency at diagnosis predicts for increased MRD and poor prognosis. The biology of LSCs has been extensively investigated and several unique properties have been identified and will be discussed below. Still, the similarities and differences between LSCs, the leukemia-initiating cells responsible for the original disease presentation and the residual leukemia cells detected after treatment in MRD assays are not fully understood. The objective of this review is to describe ongoing bench and translational research in LSCs and MRD in AML and to propose how these data should be used to change the direction of developmental therapeutics and clinical trials.
Abstract and Introduction
Abstract
Most adult patients with acute myeloid leukemia (AML) die from their disease. Relapses are frequent even after aggressive multiagent chemotherapy and allogeneic stem cell transplantation. AML is a biologically heterogeneous disease, characterized by frequent cytogenetic abnormalities and an increasing spectrum of genetic mutations and molecular aberrations. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation. These cells may persist after treatment and are probably responsible for disease relapse. This review will describe bench and translational research in LSCs and discuss how the data should be used to change the direction of developmental therapeutics and clinical trials in AML.
Introduction
Most adult patients with acute myeloid leukemia (AML) die from their disease despite achieving initial complete remission (CR), including those treated with aggressive multiagent chemotherapy and allogeneic stem cell transplantation. Numerous Phase I, II and III clinical trials of both novel and conventional agents have failed to improve overall survival for older patients and the 5-year survival for younger patients is still only approximately 40%. Thus, it is obvious in the clinic that certain leukemic cells must be fundamentally resistant to our currently available armamentarium of chemotherapy, immunotherapy and radiation. Laboratory data suggest that AML originates from a rare population of cells, termed leukemic stem cells (LSCs) or leukemia-initiating cells, which are capable of self-renewal, proliferation and differentiation into malignant blasts. At least some of these cells persist after treatment and are probably responsible for disease relapse. Clinical data show that for patients in morphologic CR, the presence of minimal residual disease (MRD), as detected by sensitive flow cytometric assays, predicts for disease relapse in AML. Furthermore, a high stem cell frequency at diagnosis predicts for increased MRD and poor prognosis. The biology of LSCs has been extensively investigated and several unique properties have been identified and will be discussed below. Still, the similarities and differences between LSCs, the leukemia-initiating cells responsible for the original disease presentation and the residual leukemia cells detected after treatment in MRD assays are not fully understood. The objective of this review is to describe ongoing bench and translational research in LSCs and MRD in AML and to propose how these data should be used to change the direction of developmental therapeutics and clinical trials.
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