Rapid Decline of Chronic Myeloid Leukemic Cells in Long-Term Culture Due to a Defect at the Leukemic Stem Cell Level

In this report we describe a quantitative in vitro assay for the most primitive type of leukemic precursors yet defined in patients with chronic myeloid leukemia (CML). This assay is based on the recently described "long-term culture-initiating cell" (LTC-IC) assay for primitive normal hum...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1992-07, Vol.89 (13), p.6192-6196
Main Authors: Udomsakdi, C., Eaves, C. J., Swolin, B., Reid, D. S., Barnett, M. J., Evans, A. C.
Format: Article
Language:English
Subjects:
Biological and medical sciences
Blood
Blood cells
Bone marrow
Bone Marrow - pathology
Cell Division
Chronic myeloid leukemia
Cultured cells
Feeder cells
Hematologic and hematopoietic diseases
Hematopoietic stem cells
Hematopoietic Stem Cells - pathology
Humans
In Vitro Techniques
Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - blood
Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Leukocytes
Medical research
Medical sciences
Multidisciplinary Sciences
Neoplastic Stem Cells - pathology
Progenitor cells
Science & Technology
Science & Technology - Other Topics
Stem cells
T lymphocytes
Time Factors
Tumor Cells, Cultured - pathology
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Description
Summary:In this report we describe a quantitative in vitro assay for the most primitive type of leukemic precursors yet defined in patients with chronic myeloid leukemia (CML). This assay is based on the recently described "long-term culture-initiating cell" (LTC-IC) assay for primitive normal human hematopoietic cells. Such cells, when cocultured with competent fibroblast feeder layers, give rise after a minimum of 5 weeks to multiple single and multilineage clonogenic progenitors detectable in secondary semisolid assay cultures. Similar cultures initiated by seeding a highly enriched source of leukemic cells from patients onto normal feeders showed the clonogenic cell output after 5 weeks to be linearly related to the input innoculum over a wide range down to limiting numbers of input cells, thus allowing absolute frequencies of leukemic LTC-ICs to be determined using standard limiting dilution analysis techniques. Leukemic LTC-IC concentrations in CML marrow were found to be decreased, on average to 105times) in CML blood. Assessment of the number of clonogenic cells produced per leukemic LTC-IC by comparison to normal blood or marrow LTC-IC values showed this function to be unchanged in leukemic LTC-ICs [i.e., 3.1 ± 0.4 clonogenic cells per CML LTC-IC (mean ± SEM, n = 6) versus 3.7 ± 1.2 (n = 3) and 4.3 ± 0.4 (n = 5), respectively, for normal blood and marrow LTC-ICs]. In contrast, leukemic LTC-IC maintenance in LTC proved to be highly defective by comparison to normal LTC-IC of either blood or marrow origin. Thus, when cells from primary LTC were subcultured into secondary LTC-IC assays, leukemic LTC-IC rapidly declined (>30-fold) within the first 10 days of culture, whereas normal LTC-IC numbers remained unchanged during this period. These findings illustrate how self-maintenance and differentiation events in primitive human hematopoietic cells can be differentially modulated by an oncogenic process and provide a framework for further studies of their manipulation, analysis, and therapeutic exploitation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.89.13.6192