Detection and clinical significance of human acute myeloid leukaemia progenitors capable of long-term proliferation in vitro

Abstract

Acute myeloid leukaemia (AML) blasts within individual patients are heterogeneous in their surface antigen expression and proliferative ability suggesting that, subsequent to transformation, differentiation occurs creating a hierarchy of progenitors in AML. Cells that can produce AML colonies (colony forming units, CFU) in growth factor containing suspension cultures (SC) over 4-8 weeks have a phenotype similar to AML progenitors that engraft non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice, but different from bulk AML blasts, suggesting that these AML SC-initiating cells (SC-IC) may be early progenitors. In this study, we evaluated culture conditions that provide for optimal growth of AML progenitors capable of long-term proliferation. The frequency of CFU, both initially and after 2-4 weeks of SC, varied over four logs between individual patients and was not related to French-American-British subtype. Using limiting dilution, the proliferative potential of individual SCIC varied from 1 to 480 CFU. The frequency of CFU from SC after > 4 weeks was prognostic for patient survival, and correlated with NOD/SCID engrafting ability. These results suggest the use of long-term culture as an assay for AML cells with leukaemia sustaining potential.