Complexity of the human acute myeloid leukemia stem cell compartment: Implications for therapy

Abstract

Emerging evidence suggests cancer stem cells CSCs) sustain neoplasms; however, little is undertood of the healthy cell initially targeted and the esultant CSCs [1-3]. The most advanced understandng comes from the hematologic malignancies because f the availability of quantitative functional assays for ormal stem cells (hematopoietic stem cells; HSCs) nd progenitor cells (colony-forming cells), as well as or leukemic stem cells (LSCs) and progenitor cells acute myeloid leukemia [AML]-colony-forming ells). Advances in the ability to identify the biological roperties of individual human HSCs and LSCs by sing retroviral-mediated clonal tracking coupled with he nonobese diabetic/severe combined immunodefiiency (NOD/SCID) mouse xenotransplantation asay have been critical to progress [4-6]. These studies emonstrated that LSCs are not functionally homoeneous but, like the normal HSC compartment, are omposed of distinct hierarchically arranged LSC lasses. Thus, the AML clone is organized as a hierrchy that originates from human SCID leukemianitiating cells (SL-ICs), which produce AML colonyorming units (AML-CFUs) and leukemic blasts. oreover, similarities between SL-ICs and normal SCs support a hypothesis that the target cell of rigin of AML LSCs often lies within the normal stem ell compartment, although, as noted below, under ome circumstances LSCs could arise through the cquisition of additional mutations in downstream rogenitors [1,3]. LSCs hold the key to understanding the origin nd maintenance of AML and possess biological proprties that are different from the bulk of the leukemic lones; this makes them difficult to eradicate. Thus, h