4 List of Abbreviations 5 Abstract Acute myeloid leukemia (AML) develops as the consequence of a series of genetic changes in a hematopoietic precursor cell, that alter normal hematopoietic growth and differentiation, resulting in an accumulation of large numbers of abnormal, immature myeloid cells in the bone marrow and peripheral blood. The deceivingly homogeneous, undifferentiated morphology of the leukemic blasts is now known to mask a heterogeneous collection of cells that recapitulate the

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... hierarchy of precursor cells that characterize the normal process of blood-cell differentiation. Leukemia-initiating cell (LIC) properties occur in a selfrenewing non-hematopoietic stem cell progenitor cell population, preceded by the expansion of a preleukemic long-term hematopoietic stem cell (LT-HSC). The WNT/β-catenin pathway has been show to play a critical role in the regulation of cell proliferation, differentiation, and apoptosis of different malignant entities. Previous results obtained by our research team provided direct evidence that the WNT/β-catenin signaling is diffusely activated in the AC133 + AML population, with a specific transcriptional signature involving overexpression of the WNT pathway agonists and down-modulation of the major antagonists. Appling the new in situ technique on AML bone marrow sections, we confirmed a dramatic increase of WNT10B expression and protein release within the microenvironment in the large majority of sample. Conversely, the activation of WNT signaling, marked by expression of the dephosphorylated β-catenin, was restricted only to a smaller subpopulation of AC133 bright cells.