Acute myeloid leukemia stem cells: seek and destroy

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.

Figure 1. Models for leukemia development and therapeutic targets

The figure represents three possible scenarios of leukemia stem cell transformation. (a) A self-renewing hematopoietic stem cell transforms by an oncogenic event to give rise to a pre-leukemia stem cell that, over time, can give rise to a fully transformed leukemia stem cell (LSC). (b) A restricted progenitor can be transformed by a mutation that confers self-renewal. The pre-leukemia stem cell progenitor is maintained and, with further mutations, gives rise to a LSC. (c) A first mutation in a restricted progenitor does not promote self-renewal. In the absence of secondary mutations, the pre-malignant cell is lost and does not give rise to a LSC. Two possible therapeutic outcomes are also depicted by the shaded triangles, showing the cells targeted by two therapeutic regimens: (1) leukemic blasts (blue shaded region); and (2) leukemic blasts, stem, progenitors cells, and potentially pre-leukemic cell types (entire triangle). LSC: Leukemic stem cell.