Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts

Abstract

SummaryCells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML.

Quantification and three-dimensional microanatomical organization of the bone marrow

“…This will also be of key importance in light of studies that demonstrate that functional and structural remodeling of the 3D tissue microenvironment are essential and necessary for malignant transformation and tumor progression in certain cancers, including those of the hematopoietic system. [70][71][72] The knowledge gained will have further implications for antineoplastic therapies and regenerative medicine. The full recapitulation of the conditions of differentiation and maintenance of HSCs in vitro, and the design of ideal strategies for hematopoietic tissue engineering, will inevitably require the complementation of comprehensive molecular and cellular data with essential information on native tissue microarchitecture.…”

Neoplasms in the bone marrow niches: disturbance of the microecosystem

“…Several studies found that deletion or mutation of functional genes in these niche cells led to MPNs, myelodysplasia, or leukemia [12,[28][29][30][31][32]. These findings and accordingly raised concepts were proved by the clinical transplantation investigations, in which donor-derived hematologic malignancies after hematopoietic stem cell transplantation were diagnosed [33].…”

Communication of bone cells with hematopoiesis, immunity and energy metabolism

“…35 Constitutive activation of b-catenin selectively in osteoblasts in mice also caused myelodysplastic syndrome/leukemia through the activation of Notch signaling in HSCs/HPCs. 36 Thus, the osteoblastic microenvironment is essential for both normal and malignant hematopoiesis.…”