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Abstract
Acute myeloid leukemia is a bone marrow disease characterized by a block in differentiation of the myeloid lineage with a concomitant uncontrolled high proliferation rate. Development of acute myeloid leukemia from stem cells with specific founder mutations, leads to an oligoclonal disease that progresses into a very heterogeneous leukemia at diagnosis. Measurement of leukemic stem cell load and characterization of these cells are essential for prediction of relapse and target identification, respectively. Prediction of relapse by monitoring the disease during minimal residual disease detection is challenged by clonal shifts during therapy. To overcome this, characterization of the potential relapse-initiating cells is required using both flow cytometry and molecular analysis since leukemic stem cells can be targeted both on extracellular features and on stem-cell specific signal transduction pathways.
Financial & competing interests disclosure
The authors were funded by VONK and the Dutch Cancer Society (#2005-3666). GJ Schuurhuis has filed a patent request ‘Leukemic stem cell markers’ #2011904. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Key issues
Since the development of relapse after first complete remission is the major factor of treatment failure, the best way to improve acute myeloid leukemia (AML) outcome is the prevention and/or eradication of the relapse.
Minimal residual disease (MRD) is essential for determining treatment response and monitoring of disease, however, still a substantial proportion of MRDlow patients relapse.
False-negative MRD results can be explained by: presence of leukemic stem cell (LSC), which can be identified by stem cell markers (immunophenotypic [CD34+/CD38−] and functional markers [side population and aldehyde dehydrogenase]) supplemented with aberrant leukemia-specific markers and the selection and outgrowth of sub-clones with different immunophenotypical aberrant markers.
Further characterization of MRD by LSC measurements improves the prediction of outcome; high LSC burden at diagnosis and persistence during therapy are strongly associated with poor prognosis.
AML is an oligoclonal disease and the heterogeneity is extensive in the immature sub-populations.
Clonal selection of very small drug-resistant clones with self-renewal capacity that survive treatment are probably the relapse-initiating cells.
Multiparameter flow cytometry is required to accurately detect LSC.
Several novel stem cell-targeted therapies are currently under investigation with the objective to completely eradicate all AML cells and prevent the development of relapse.