Abstract:

Our conceptual view on cancer evolution has changed dramatically over the past decade. By enlarge, this is due to development of new technology that allows to measure genomic, transcriptomic and proteomic features at the single cell level. Based on these new insights we now know that, in contrast to what previously dogmatically proposed, many cancers including acute myeloid leukemia (AML) do not evolve along a linear evolutionary path. Rather, these blood cancers display branching evolutionary patterns whereby multiple genetically distinct clones can co-exist.^1-4 Since such subclones are genetically distinct, their biology, transcriptional programs and drug sensitivities also differ.¹ This heterogeneous complexity clearly hampers treatment strategies. Indeed, cure rates in AML patients are still unacceptably low, with 5 year survival rates of around 25%. A second level of heterogeneity can be found in the tumor immune microenvironment. For instance, we recently uncovered that the macrophage landscape in AML can be remarkably different between individual patients. While the bone marrow (BM) of some patients predominantly harbors tumor suppressive M1-polarized macrophages, others are dominated by tumor supportive M2-polarized macrophages. The latter patient group is also characterized by the poorest survival. Functionally, we showed that M2 macrophages strongly support leukemic transformation and impose drug resistance, both in vitro as well as in vivo in transplantation studies in xenograft models. We uncovered that leukemic stem cells and macrophages form intricate interactions in a process we call “macrophage cuddling”, during which leukemic cells obtain immune evasive properties and alter their metabolism, in part by hijacking mitochondria from macrophages. Based on the relevant roles of M2 macrophages in leukemia development we have developed a novel flow cytometry-based prognostic signature that is better in predicting prognosis of AML patients compared to currently used predictors.