Abstract A29: High aldehyde dehydrogenase activity is general marker for normal hematopoietic stem cells but not leukemic stem cells in acute myeloid leukemia
Authors: Jan Schuurhuis Gerrit , Min Lisa , Terwijn Monique , Kelder Angele , Snel Sander , Ossenkoppele Gert , Smit Linda 
Published: January 2011

Only a minority of cells, the leukemic stem cells (LSCs), within Acute Myeloid Leukemia (AML) are typically responsible for tumor growth and maintenance. Many patients experience a relapse after therapy which originates mainly from the outgrowth of therapy resistant LSC. Therefore, eradication of the LSCs is likely necessary to cure leukemia. Both the normal hematopoietic stem cells (HSCs) and LSCs co-exist in the bone marrow (BM) of leukaemia patients and therefore success of an anti-stem-cell strategy relies on specific induction of LSC death while sparing the normal HSC. In AML, apart from the CD34+CD38- and the side population (SP) compartment, the high aldehyde dehydrogenase (ALDH) activity compartment contains the LSCs. ALDH is a detoxifying enzyme responsible for the oxidation of intracellular aldehydes. Recent data has shown that ALDH is highly expressed in both normal progenitor and stem cells and in AML blast cells. High ALDH activity results in resistance to alkylating agents such as the active derivatives of cyclophosphamide.

We have previously shown that CD34+CD38- and SP LSCs can be identified and discriminated from HSCs using stem cell-associated cell surface markers, including C-type lectin-like molecules (CLL-1), lineage markers, such as CD7, CD19, and CD56 and recently cell size characteristics as measured by flow cytometry. Here we have analyzed ALDH activity in normal HSCs and LSCs, both present within the same BM, in 23 AML patient samples. In 7 AML cases, a high SSCloALDHbr cell population was identified (&gt;5%).

We show that in 9 BM AML samples, defined as CD34min (ie &lt;1% CD34+ cells, in which the CD34+CD38-cells are all normal HSC), the ALDH activity is lower in the LSC then in the HSC. The activity of the normal HSC within this AML BM is identical as the ALDH activity of normal HSC in NBM of healthy donors. In 9 BM AML patients, defined as CD34+ and with both normal and leukemic CD34+CD38-present, we show that the marker positive CD34+CD38-LSCs have lower ALDH activity then the marker negative CD34+CD38-HSCs. Altogether, we show that, although malignant AML blast cells have varying ALDH activity, a common feature of all AML cases is that the normal HSCs that co-exist with leukemic (stem) cells in the BM of AML patients have a higher ALDH activity as compared to their malignant counterparts.

In conclusion, high ALDH activity is an unique marker of normal HSC within the AML BM at diagnosis. Consequently, AML patients with high ALDH activity in the normal HSC might benefit from treatment with alkylating agents such as mafosfamide, whereby the difference between the ALDH activity in LSC and HSC defines the therapeutic window. At present, drugs, known to be dependent on low ALDH for proper activity, are tested for their LSC specific killing while sparing the normal HSC.

Citation Information: Clin Cancer Res 2010;16(7 Suppl):A29