The Osteoblast as a Determinant of Leukemogenesis

描述(申请人提供)：除了它们的骨构建特性，成骨细胞还通过影响造血干细胞(HSCs)的更新和扩张而参与造血。最近，成骨细胞前体参与了另一种干细胞--白血病母细胞的命运。我们发现，成骨细胞前体中典型的Wnt信号的激活突变通过改变HSC前体细胞向髓系的分化潜能和粒细胞/单核细胞前体细胞的聚集来扰乱小鼠的造血。随之而来的是，B淋巴细胞的生成受到了影响。这种表型使人联想到人类骨髓发育不良，并最终导致急性髓系白血病(AML)的发展和早期死亡。我们假设，成骨细胞前体中b-连环蛋白的稳定导致AML以Notch信号依赖的方式发展。导致HSCs致癌转化的其他独立事件可能涉及染色体异常和表观遗传学改变。这项应用表明，成骨细胞特异性激活b-连环蛋白是导致功能障碍的造血和急性髓系白血病发生的原因。此外，它还将研究Notch信号在介导成骨细胞中b-连环蛋白激活的白血病特性中的作用。最后，它将通过检测基因表达调控的变化以及HSC群体中遗传和表观遗传学异常的存在来评估恶性转化信号的性质。这些研究可能确定成骨细胞是急性髓系白血病的决定因素。

DESCRIPTION (provided by applicant): In addition to their bone building properties, osteoblasts have been implicated in hematopoiesis by affecting renewal and expansion of hematopoietic stem cells (HSCs). More recently, osteoblast precursors have been involved in the fate of another stem cell, the leukemia blast. We have found that an activating mutation in canonical Wnt signaling in osteoblast precursors disrupts hematopoiesis in mice by altering the differentiation potential of HSC progenitors to the myeloid lineage and accumulation of granulocyte/monocyte progenitors. Concomitantly, B- lymphopoiesis is compromised. This phenotype is reminiscent of human myelodysplasia and eventually leads to the development of acute myeloid leukemia (AML) and early lethality. We hypothesize that stabilization of b-catenin in osteoblast precursors leads to AML development in a Notch signaling-dependent manner. Additional and independent events leading to oncogenic transformation of HSCs may involve chromosomal aberrations and epigenetic alterations. This application proposes to establish that osteoblast-specific activation of b-catenin is responsible for dysfunctional hematopoiesis and AML development. In addition, it will investigate the involvement of Notch signaling in mediating the leukemogenic properties of b-catenin activation in osteoblasts. Finally, it will evaluate the nature of the malignant transformation signal by examining changes in gene expression-regulation and the presence of genetic and epigenetic abnormalities in the HSC population. These studies may identify the osteoblast, as a determinant of AML.