Immunosurveillance during the formation and progression of AML

Abstract

Despite progress in the treatment of acute leukemia, specific subtypes still have a very bad prognosis, highlighting the need for increased knowledge that can be harnessed to develop novel therapeutic strategies. While experimental data from the last decade have conclusively established that the immune system can critically influence on the development of cancer, with a range of immunomodulatory strategies reaching clinical use, most studies have been conducted using solid cancer models of non-hematological origin. Such cancers evidently have requirements very distinct from hematological cancers that pertain to initiation, maintenance and spreading (metastasis). Also, constraints of experimental models precluding spatiotemporal control have to a large extent hindered investigations of immunosurveillance and immunoediting mechanisms during the multistep progression of acute leukemia. Here, we make use of a recently described mouse model of acute myeloid leukemia AML (Ugale et al, 2014) in which physiologically relevant expression levels of the fusion oncogene MLL-ENL can be conditionally activated in vivo as a leukemic “first-hit”. This model associates with a phase of “pre-leukemic” contraction after which overt clonal transformation commences, highlighting the critical influence of secondary but less defined events during the course of disease. By investigating aspects of the immune system during the formation and progression of AML, we show that transformation follows similar kinetics regardless of developing in wild type (WT) or immune-deficient (Rag2-/- or Rag2-/gc-/-) environments. By contrast, immunity critically influences on the propagation of established leukemia, but with little evidence of primary immune-editing. Rather, intrinsic properties of individual leukemic clones, regardless of their origin, underlie the aggressiveness of arising disease. Antibody-mediated in vivo depletion experiments revealed a critical role for CD8+ cells in this process. Ongoing investigations focus on analyzing and characterizing CD8+ T lymphocyte subsets during the disease course of AML.