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Blood, 15 August 2001, Vol. 98, No. 4, pp. 1166-1173
NEOPLASIA
A leukemic stem cell with intrinsic drug efflux capacity in
acute myeloid leukemia
Gerald G. Wulf,
Rui-Yu Wang,
Ingrid Kuehnle,
Douglas Weidner,
Frank Marini,
Malcolm K. Brenner,
Michael Andreeff, and
Margaret A. Goodell
From the Center for Cell and Gene Therapy, Baylor
College of Medicine; and Molecular Hematology and Therapy, M. D. Anderson Cancer Center, Houston, TX.
The hematopoietic stem cell underlying acute myeloid leukemia (AML)
is controversial. Flow cytometry and the DNA-binding dye Hoechst 33342 were previously used to identify a distinct subset of murine
hematopoietic stem cells, termed the side population (SP), which
rapidly expels Hoechst dye and can reconstitute the bone marrow of
lethally irradiated mice. Here, the prevalence and pathogenic
role of SP cells in human AML were investigated. Such cells were found
in the bone marrow of more than 80% of 61 patients and had a
predominant CD34low/ immunophenotype. Importantly, they
carried cytogenetic markers of AML in all 11 cases of active disease
examined and in 2 out of 5 cases in complete hematological remission.
Comparison of daunorubicin and mitoxantrone fluorescence emission
profiles revealed significantly higher drug efflux from leukemic SP
cells than from non-SP cells. Three of 28 SP cell transplants generated
overt AML-like disease in nonobese diabetic-severe combined
immunodeficient mice. Low but persistent numbers of leukemic SP
cells were detected by molecular and immunological assays in half of
the remaining mice. Taken together, these findings indicate that SP
cells are frequently involved in human AML and may be a target for
leukemic transformation. They also suggest a mechanism by which SP
cells could escape the effects of cytostatic drugs and might eventually contribute to leukemia relapse.
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