Prevalence and Growth Characteristics of Malignant Stem Cells in B-Lineage Acute Lymphoblastic Leukemia

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Abstract
We used a stroma-supported culture method to study the prevalence and growth characteristics of malignant stem cells in acute lymphoblastic leukemia (ALL). In 51 of 108 B-lineage ALL samples, bone marrow-derived stroma not only inhibited apoptosis of ALL cells but also supported their proliferation in serum-free medium. When single leukemic cells were placed in the stroma-coated wells of microtiter plates, the percentage of wells with leukemic cell growth after 2 to 5 months of culture ranged from 6% to 20% (median, 15%; 5 experiments). The immunophenotypes and genetic features of cells recovered from these cultures were identical to those noted before culture. All cells maintained their stroma dependency and self-renewal capacity. Leukemic clones derived from single cells contained approximately 103 to 106 cells after 1 month of culture; other clones became detectable only after prolonged culture. Cell growth in stroma-coated wells correlated with the number of initially seeded cells (1 or 10; r = .87). However, the observed percentages of positive wells seeded with 10 cells always exceeded values predicted from results with single-cell–initiated cultures (P < .003 by paired t-test), suggesting stimulation of leukemic cell growth by paracrine factors. In conclusion, the proportion of ALL cells with clonogenic potential may be considerably higher than previously thought.

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