aCGH analysis was performed in the spleen of βcat(ex3)osb mice

Cells of the osteoblast lineage affect homing, number of long term repopulating hematopoietic stem cells (HSCs) HSC mobilization and lineage determination and Blymphopoiesis . More recently osteoblasts were implicated in pre-leukemic conditions in mice. Yet, it has not been shown that a single genetic event taking place in osteoblastscan induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin leading to development of acute myeloid leukemia (AML) with common chromosomal aberrationsand cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSCprogenitors induces the malignant changes. Demonstrating the pathogenetic role of theNotch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% ofpatients 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 pharmacotherapeuticapproach to AML. The present entry describes a comparison of copy numbers of DNA from βcat(ex3)osb mice from the mouse spleen with that of WT (C57BL/J Mice) mice. DNA from spleen myeloid cells from βcat(ex3)osb mice and WT mice were hybridized to Agilent CGH 244A arrays. DNA from spleen myeloid cells from βcat(ex3)osb mice in C57BL/J background was labeled with red dye. DNA from spleen myeloid cells from WT (C57BL/J) mice were labeled with green dye. There were five arrays with DNA from 1 mouse of each genotype per array.

成骨细胞系（osteoblast lineage）可影响长期重建造血干细胞（long-term repopulating hematopoietic stem cells, HSCs）的归巢、数量，以及造血干细胞的动员、谱系定向与B淋巴细胞生成（B lymphopoiesis）。近年来研究发现，成骨细胞（osteoblasts）与小鼠的白血病前期状态相关，但此前尚无研究证实，成骨细胞内的单遗传事件即可诱发白血病发生（leukemogenesis）。本研究证实，在小鼠体内，β-连环蛋白（β-catenin）的激活突变可导致伴有常见染色体畸变的急性髓系白血病（acute myeloid leukemia, AML）发生，并伴随细胞自主性进展。激活的β-连环蛋白可促进成骨细胞中Notch配体（Notch ligand）Jagged-1的表达，随后激活造血干细胞祖细胞（HSC progenitors）中的Notch信号通路，进而诱导恶性改变。通过证实Notch通路的致病作用，研究发现对Notch信号通路进行遗传或药物抑制可缓解AML病情。在38%的骨髓增生异常综合征/急性髓系白血病（myelodysplastic syndromes/acute myeloid leukemia, MDS/AML）患者中，也可观察到成骨细胞的核积累与β-连环蛋白信号增强；此类患者的造血细胞中Notch信号水平也有所升高。上述研究结果证实，成骨细胞的遗传改变可诱发AML，明确了介导这一转化的分子信号通路，并为AML提供了一种潜在的新型药物治疗策略。本数据集旨在比较βcat(ex3)osb小鼠与野生型（wild type, WT）C57BL/J小鼠脾脏DNA的拷贝数差异：将C57BL/J背景下的βcat(ex3)osb小鼠脾脏髓系细胞的DNA以红色染料标记，野生型C57BL/J小鼠脾脏髓系细胞的DNA以绿色染料标记，随后将两组DNA分别与安捷伦CGH 244A芯片阵列（Agilent CGH 244A arrays）进行杂交。本实验共设置5张芯片阵列，每张阵列分别使用对应基因型各1只小鼠的脾脏髓系细胞DNA。