Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid LeukemiaReport as inadecuate




Normal Hematopoietic Progenitor Subsets Have Distinct Reactive Oxygen Species, BCL2 and Cell-Cycle Profiles That Are Decoupled from Maturation in Acute Myeloid Leukemia - Download this document for free, or read online. Document in PDF available to download.

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 SPC 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 SPC, 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-SPC although they were ki67high. BCL2 upregulation was specific to GMPs. This profile was also observed for CD34+SPC 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-SPC had similar ROS levels to co-existing immature-SPC. However ROS levels varied between AMLs; Flt3ITD+-NPM1wild-type CD34+SPC had higher ROS than NPM1mutated CD34+ or CD34− SPC. An aberrant ki67lowBCL2high immunophenotype was observed in CD34+AML most prominent in Flt3ITD 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 SPC 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.



Author: Naeem Khan , Robert K. Hills, Steve Knapper, Lora Steadman, Ushna Qureshi, Jerrald L. Rector, Charlotte Bradbury, Nigel H. Russel

Source: http://plos.srce.hr/



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