Steven Grant, MD
Dr. Grant indicated no relevant conflicts of interest.
Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34 minus fraction. Blood. 2010;115:1976-1984.
Cancer stem cells (CSCs), i.e., a subset of cancer cells that display an unlimited capacity to undergo self-renewal and to give rise to a more phenotypically diverse malignant cell population, are the subject of intense interest and, to a certain extent, controversy. While some argue against the significance or even existence of these cells, there is a general consensus that if such cells exist, leukemia stem cells (LSCs), or leukemia-initiating cells (LICs), represent their prototype. Accordingly, extensive efforts are currently underway to characterize LICs, with the ultimate goal of developing strategies to eliminate them.
The initial characterization of LICs as cells expressing CD34 and lacking CD38 was described by the pioneering work of John Dick and colleagues. They discovered that cells capable of initiating leukemia in immunodeficient SCID mice resided within the CD34+, CD38- population and postulated that such cells represented true LICs. Recently, this concept was challenged when Bonnet and colleagues from London reported that antibodies directed against CD38 inhibited engraftment of LICs in SCID mice,1 suggesting that, at least in some cases, LICs may reside in the CD38+ population. In this new paper from Bonnet’s group, they showed that in certain types of leukemia LICs may, contrary to all conventional wisdom, emanate from the CD34- cell fraction. Specifically, they reported that in nucleophosmin (NPM)-mutated AML, the cells capable of initiating leukemia in SCID mice resided exclusively in the CD34- fraction in half of the cases. In the remaining cases, considerable heterogeneity was observed; some exhibited a more primitive phenotype (CD34+, CD38-), whereas others displayed a more progenitor-like phenotype (CD34+, CD38+). One possible explanation for these novel findings lies in the fact that leukemia cells from patients with a poor prognosis are more likely to initiate leukemia in immunodeficient mice. Because NPM-mutated leukemia carries a generally favorable prognosis, less information about the characterization of LICs in this subtype has been available. In any case, these new findings make several important points: the phenotype of LICs may be considerably more heterogeneous than previously thought, and such disparate phenotypes can in fact co-exist within individual leukemia cell samples.
These new findings could have significant implications for attempts to eradicate LICs with targeted therapies, particularly those employing approaches directed against leukemia cell surface antigens. They could also prompt a reappraisal of the optimal use of molecularly targeted agents to eliminate LICs. Although it has not yet been definitively proven, the concept that residual LICs are responsible for or contribute to relapse in AML remains plausible and unquestionably needs to be tested. However, until and unless LICs can be clearly defined, such efforts may be doomed to fail. To test the leukemia stem cell hypothesis definitively, it may be necessary to define LICs in relation to the genetic background of the AML subtype in question, and possibly even in individual patients. Despite the questions raised by this report, the findings presented could ultimately lead to more rational (and hopefully more effective) approaches to leukemia therapy.
- Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody–mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568-575.
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