ALDH marks leukemia stem cell

ALDH activity has been touted as a marker for normal and malignant stem cells, not only in the hematopoietic system^2,,–5  but also in solid organs such as breast,⁶  colon,⁷  and ovary.⁸  Normal bone marrow CD34⁺CD38⁻ cells can be subdivided into 2 nonoverlapping populations based on ALDH staining (high and low), with the ability to engraft immunodeficient mice restricted to the ALDH^high population. Gerber et al now demonstrate that AML patient bone marrow contains an additional subpopulation with intermediate ALDH activity (ALDH^int; see figure).¹  This population is absent in normal control bone marrow. It is important to note that the ALDH^int population is not necessarily a ubiquitous feature of AML; it was not present in 4 of the 20 newly diagnosed AML patients studied.

The ALDH^int population fits the bill for the LSC compartment: as few as 1000 cells engraft leukemia into immunodeficient mice. The ALDH^int population is uniformly positive for the clonal leukemic cytogenetic marker. Like the ALDH^int population, cells within the ALDH^low population also contain the diagnostic leukemia cytogenetic marker, but in contrast to ALDH^int cells cannot engraft immunodeficient mice. This suggests that cells contained within the ALDH^low population are the leukemic progeny of the ALDH^int population.

The ALDH^high population in AML patients is a reservoir of “normal” hematopoietic stem cells. This population is devoid of cytogenetic abnormalities and as few as 1000 cells engraft normal, nonleukemic hematopoiesis into immunodeficient mice, similar to the ALDH^high population of normal bone marrow. Theoretically, on the basis of ALDH activity one could delicately separate out and collect normal hematopoietic stem cells amid a sea of leukemic cells.

Perhaps the most clinically relevant finding is that persistence of the aberrant ALDH^int population after therapy was highly predictive of subsequent relapse. The authors followed 11 AML patients who achieved morphologic complete remission (CR) after induction chemotherapy. Of the 7 patients who consistently lacked the aberrant ALDH^int population, none have relapsed (average duration of follow-up 509 days). In contrast, of 4 patients in whom the ALDH^int population was detected, all 4 have subsequently relapsed. Perhaps detection of this aberrant population could be exploited as a measure of residual disease and could potentially be used to guide therapy.

ALDH activity has also been applied to investigate the ontogeny of the JAK2^V617F clone in chronic myeloproliferative neoplasms (MPNs).⁹  In all 9 JAK2^V617F-positive patients investigated, the ALDH^high population was composed of cells bearing the JAK2^V617F mutation, demonstrating that the mutation arises in a primitive hematopoietic progenitor. In the chronic phase of the disease the ALDH^int population was absent, but subsequently appeared coincident with transformation to acute leukemia in 2 patients. This data further support the specificity of the ALDH^int population to AML and its appearance as a herald of acute leukemia.