REGENERATION-ASSOCIATED WNT SIGNALING ACTIVATION IN ACUTE MYELOID LEUKEMIA

Ample evidence exists in mouse models that acute myeloid leukemia (AML) develops through stepwise acquisition of collaborating genetic and epigenetic changes in self-renewing leukemia-initiating cells (LICs) that exhibit a committed myeloid immunophenotype. Recently, critical questions emerged regarding the characterization of LICs in the CD34+CD38- fraction and the AC133 antigen (a glycosylation-dependent epitope of CD133) seems to be one of the markers more appropriate to enrich for the LICs-containing fraction. The requirement of the Wnt/β-catenin pathway in the pathogenesis of acute myeloid leukemia (AML) has recently emerged in mouse models. However, its relationship to genetic programs promoting retention of self-renewing leukemia stem cells (LSCs) remains elusive. Hence, the need to identify transcriptional programs involved in the maintenance of a self-renewing state in LSCs. Given the predominant role of transcription factors (TFs) function in myeloid leukemia and recent progresses in reprogramming research for a critical role of TFs in the establishment and maintenance of cellular phenotypes, here we generated a specially designed transcriptional regulators (TRs) dataset to interrogate expression microarray data obtained from AC133+ cells in AML patients and healthy donors. Our data suggest that the canonical Wnt/β-catenin signaling is activated in leukemic human long-term reconstituting AC133+ restricted cells. In a series of molecular and functional studies we found that leukemic cells AC133+ synthesize and secrete WNT10B, a hematopoietic stem cells (HSCs) regenerative-associated molecule, and increase the levels of dephosphorylated β-catenin. Nevertheless, AML AC133+ cells, in zebrafish embryos, are able to develop ectopic structures by activating organizer markers that act downstream of the Wnt pathway. In light of the long-known association between cancer and chronic tissue injury, and because of the higher homeostatic range of Wnt/β-catenin signaling occurring during regeneration upon an acute injury, altogether our data provide compelling evidence that regenerationassociated Wnt signaling exceeds the homeostatic range in human AML and affects responsive cells whose renewal is promoted by Wnt pathway activity.