γ-catenin contributes to leukemogenesis induced by AML-associated translocation products by increasing the self-renewal of very primitive progenitor cells

Acute myeloid leukemia (AML) is characterized by the block of differentiation, deregulated apoptosis, and an increased self-renewal of hematopoietic precursors. It is unclear whether the self-renewal of leukemic blasts results from the cumulative effects of blocked differentiation and impaired apoptosis or whether there are mechanisms directly increasing self-renewal. The AML-associated translocation products (AATPs) promyelocytic leukemia/retinoic acid receptor α (PML/RARα), promyelocytic leukemia zinc finger (PLZF)/RARα (X-RARα), and AML-1/ETO block hematopoietic differentiation. The AATPs activate the Wnt signaling by up-regulating γ-catenin. Activation of the Wnt signaling augments self-renewal of hematopoietic stem cells (HSCs). Therefore, we investigated how AATPs influence self-renewal of HSCs and evaluated the role of γ-catenin in the determination of the phenotype of HSCs expressing AATPs. Here we show that the AATPs directly activate the γ-catenin promoter. The crucial role of γ-catenin in increasing the self-renewal of HSCs upon expression of AATPs is demonstrated by (i) the abrogation of replating efficiency upon hindrance of γ-catenin expression through RNA interference, and (ii) the augmentation of replating efficiency of HSCs upon overexpression of γ-catenin itself. In addition, the inoculation of γ-catenin-transduced HSCs into irradiated recipient mice establishes the clinical picture of AML. These data provide the first evidence that the aberrant activation of Wnt signaling by the AATP decisively contributes to the pathogenesis of AML. (Blood. 2004;103:3535-3543)