Abstract
Persistence of leukemic stem cells (LSC) after chemotherapy is thought to be responsible for relapse and prevents the curative treatment of acute myeloid leukemia (AML) patients. LSC and normal hematopoietic stem cells (HSC) share many characteristics and co-exist in the bone marrow of AML patients. For the development of successful LSC-targeted therapy, enabling eradication of LSC while sparing HSC, the identification of differences between LSC and HSC residing within the AML bone marrow is crucial. For identification of these LSC targets, as well as for AML LSC characterization, discrimination between LSC and HSC within the AML bone marrow is imperative. Here we show that normal CD34+CD38– HSC present in AML bone marrow, identified by their lack of aberrant immunophenotypic and molecular marker expression and low scatter properties, are a distinct sub-population of cells with high ALDH activity (ALDHbright). The ALDHbright compartment contains, besides normal HSC, more differentiated, normal CD34+CD38+ progenitors. Furthermore, we show that in CD34-negative AML, containing solely normal CD34+ cells, LSC are CD34– and ALDHlow. In CD34-positive AML, LSC are also ALDHlow but can be either CD34+ or CD34–. In conclusion, although malignant AML blasts have varying ALDH activity, a common feature of all AML cases is that LSC have lower ALDH activity than the CD34+CD38– HSC that co-exist with these LSC in the AML bone marrow. Our findings form the basis for combined functionally and immunophenotypically based identification and purification of LSC and HSC within the AML bone marrow, aiming at development of highly specific anti-LSC therapy.
Highlights
A small subpopulation of cells within acute myeloid leukemia (AML) is responsible for sustaining the leukemia [1]
We focussed on differences in Aldehyde dehydrogenases (ALDHs) activity between hematopoietic stem cells (HSC) and leukemic stem cells’’ (LSC), whereby we identified a small population of high ALDH activity normal HSC
We have identified the activity of ALDH enzymes as a consistent functional discrimination between LSC and HSC concomitantly present in the bone marrow (BM) of both CD34-negative
Summary
A small subpopulation of cells within acute myeloid leukemia (AML) is responsible for sustaining the leukemia [1]. This small subpopulation of leukemia-maintaining cells share cell surface markers with normal hematopoietic stem cells (HSC) and are capable of self-renewal and differentiation which has given them the name ‘‘leukemic stem cells’’ (LSC). Despite high remission rates after chemotherapy, only 30–40% of AML patients survive five years after diagnosis [2]. We have shown that high frequencies of CD34+CD38– LSC at diagnosis and after treatment predict relapse in AML [3,5]. The eradication of LSC may prevent relapse and significantly improve long-term AML outcome
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