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Blood, Vol. 94 No. 5 (September 1), 1999:
pp. 1761-1772
Growth Characteristics of Acute Myelogenous Leukemia Progenitors
That Initiate Malignant Hematopoiesis in Nonobese Diabetic/Severe
Combined Immunodeficient Mice
Laurie E. Ailles,
Brigitte Gerhard,
Hiroyuki Kawagoe, and
Donna E. Hogge
From the Terry Fox Laboratory, British Columbia Cancer Agency,
Vancouver, BC, Canada; and the Departments of Medicine and Medical
Genetics, University of British Columbia, Vancouver, BC, Canada.
The use of immunodeficient mice, particularly of the nonobese
diabetic/severe combined immunodeficient (NOD/SCID)
strain, has allowed detection of very primitive malignant progenitors from patients with acute myelogenous leukemia (AML). To define the
sensitivity and reproducibility with which the engraftment of different
AML cells can be detected, 61 different samples from patients with
newly diagnosed AML representing a variety of cytogenetic and
French-American-British (FAB) subtypes were injected into NOD/SCID
mice. Eight weeks after intravenous injection of 107 AML
cells, the average percent of human cells in mouse bone marrow was
13.3%, with 70% of samples showing easily detectable engraftment of
CD45+ cells. AML samples with cytogenetic changes
associated with a poor clinical prognosis tended to engraft to higher
levels than those with changes associated with a good prognosis. Cells
with FAB subtypes M3 and, to a lesser extent, M2, engrafted more poorly (P = .002 and .06, respectively) than those from other
subtypes. Intraperitoneal injection of human interleukin-3 and Steel
factor thrice weekly for 4 weeks did not enhance the levels of AML cell engraftment. However, AML samples that showed cytokine-independent colony growth in methylcellulose assay or expressed growth-factor mRNA
in malignant blasts achieved significantly higher levels of engraftment
than those which were cytokine dependent in culture or failed to
express cytokine message (P < .03 and P < .02, respectively). In 6 patient samples, the frequency of NOD/SCID
leukemia-initiating cells (NOD/SL-IC) varied from 0.7 to 45 per
107 cells, which was 200- to 800-fold lower than the
frequency of AML long-term culture-initiating cells (AML LTC-IC) in the
same samples. Each NOD/SL-IC will produce more than 106
leukemic blasts as well as many AML-CFC and AML LTC-IC as detected 8 weeks postinjection into mice. Serial transplant experiments showed the
ability of NOD/SL-IC to maintain their own numbers over at least 3 to 4 weeks in vivo. The ability of these progenitors to self-renew combined
with their potential to differentiate to produce large numbers of more
mature progenitors and leukemic blasts suggests that the NOD/SL-IC
assay identifies leukemic `stem cells' that may maintain the
malignant clone in human patients. The further use of this assay should
facilitate studies of AML stem cell biology and the evolution of novel
therapeutic strategies.
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