Leukemogenic Transformation of Hematopoietic Cells by Constitutive Activation of Canonical Wnt Signaling in Osteoblast Precursors

Abstract 509

Osteoblasts, the bone forming cells, are implicated in the fate of healthy and malignant stem cells. They affect self-renewal and expansion of hematopoietic stem cells (HSCs) and homing of tumor cells into the bone marrow. Here we show that constitutive activation of canonical Wnt signaling in osteoblast precursors disrupts hematopoiesis in mice by shifting the differentiation potential of HSC progenitors to the myeloid lineage which results in accumulation of granulocyte/monocyte progenitors and concomitant development of acute myeloid leukemia (AML). B-lymphopoiesis is also decreased. The AML phenotype is associated with clonal evolution at the cytogenetic level since clonal abnormalities could be detected in leukemic blasts from mice with constitutive activation of the canonical Wnt target β-catenin in osteoblast precursors (βcatenin_osb mice). Bone marrow transplantation experiments from βcatenin_osb mice to wild type lethally irradiated mice resulted in development of AML within 8 weeks following transplantation, demonstrating progression towards AML. At the molecular level, cell-specific gene inactivation mouse models demonstrate that β-catenin interacts with FoxO1 in osteoblasts to induce development of AML. Downstream signaling events that confer osteoblast signaling to normal HSCs and lead to their leukemogenic transformation will be presented. Importantly, malignancy-inducing osteoblasts, detected by nuclear accumulation of β-catenin in bone marrow biopsies, were identified in > 25% of patients with myelodysplasia (MDS), acute myeloid leukemia (AML) or AML arising from a prior MDS. Specifically, 15 out of 53 patients with MDS (n=17 patients), AML (n=20 patients), or MDS that had transformed to AML (n=16) chosen at random showed nuclear localization of β-catenin in osteoblasts. Of note, 12 of the 15 (80%) patients with nuclear localization of β-catenin in osteoblasts had abnormalities of chromosome 5 and/or 7, very common cytogenetic abnormalities in patients with MDS and AML. The same signaling pathways mediating AML development in βcatenin_osb mice were also found to be activated in osteoblasts and hematopoietic cells from the patients with nuclear accumulation of β-catenin in osteoblasts. These findings demonstrate that genetic alterations in osteoblast precursors (1) can induce AML in mice and (2) are associated with AML development in humans. They also provide a molecular basis for the leukemogenic transformation.