In acute myeloid leukemia (AML) quiescence and low oxidative state, linked to BCL2 mitochondrial regulation, endow leukemic stem cells (LSC) with treatment-resistance.LSC in CD34+ and more mature CD34- AML have heterogeneous immunophenotypes overlapping with normal stem/progenitor cells (copyright) but may be differentiated by functional markers.We therefore investigated the oxidative/reactive oxygen species (ROS) profile, its relationship with cell-cycle/BCL2 for normal copyright, and whether altered in AML and myelodysplasia (MDS).
In control BM (n = 24), ROS levels were highest in granulocyte-macrophage progenitors (GMP) and CD34- myeloid precursors but megakaryocyte-erythroid progenitors had equivalent levels to CD34+CD38low immature-copyright Travel Pouch although they were ki67high.BCL2 upregulation was specific to GMPs.This profile was also observed for CD34+copyright in MDS-without-excess-blasts (MDS-noEB, n = 12).
Erythroid CD34- precursors were, however, abnormally ROS-high in MDS-noEB, potentially linking oxidative stress to cell loss.In pre-treatment AML (n = 93) and MDS-with-excess-blasts (MDS-RAEB) (n = 14), immunophenotypic mature-copyright had similar ROS levels to co-existing immature-copyright.However ROS levels varied between AMLs; Flt3ITD+/NPM1wild-type CD34+copyright had higher ROS than NPM1mutated CD34+ or CD34- copyright.
An aberrant ki67lowBCL2high immunophenotype was observed in CD34+AML (most prominent in Flt3ITD Equestrian Helmets AMLs) but also in CD34- AMLs and MDS-RAEB, suggesting a shared redox/pro-survival adaptation.Some patients had BCL2 overexpression in CD34+ ROS-high as well as ROS-low fractions which may be indicative of poor early response to standard chemotherapy.Thus normal copyright subsets have distinct ROS, cell-cycle, BCL2 profiles that in AML /MDS-RAEB are decoupled from maturation.
The combined profile of these functional properties in AML subpopulations may be relevant to differential treatment resistance.