Targeting osteoblasts to inhibit AML

 描述(申请人提供)：急性髓系白血病急需新的治疗方法。治疗耐药的AML细胞明显受到骨髓骨内壁龛的保护。这项建议旨在为旨在抑制保护AML细胞的骨髓微环境的细胞机制的新疗法的开发提供基础。我们最近发现，分化的成骨细胞，而不是成骨前体细胞或终末分化的骨细胞，能够保护AML细胞免受包括骨髓微环境中其他细胞分泌的SDF-1(CXCL12)诱导的凋亡的影响。此外，我们的初步数据表明，分化的成骨细胞也保护AML细胞免受化疗诱导的凋亡。有趣的是，我们的结果表明，骨祖细胞向成骨细胞分化的早期阶段是允许这些细胞保护AML细胞的关键。抑制成骨细胞分化的特定阶段(S)可以保护AML细胞免受SDF-1或化疗诱导的凋亡，这可能会增强目前治疗AML的疗效。遗憾的是，成骨细胞分化的这一“保护性”阶段目前还没有明确的定义。在这里，我们建议使用我们的体外共培养系统和AML的小鼠模型来验证我们的假设，即抑制成骨细胞分化将显著削弱骨内骨髓利基保护AML细胞的能力。我们的目的是1)通过特征性的基因改变来干扰特定的成骨细胞分化阶段，以便在体外骨髓共培养模型中确定能够保护急性髓细胞白血病细胞的成骨细胞发育的特定阶段(S)，以及2)确定急性髓细胞白血病细胞在成骨细胞分化不足的小鼠骨髓微环境中的存活率和定位，并评估其对急性髓细胞白血病疾病严重程度和复发率的影响。结合起来，这些研究将检验我们的假设，并确定成骨细胞分化的特定阶段(S)，该阶段介导了对急性髓细胞白血病细胞免受SDF-1和化疗诱导的凋亡的保护。

 DESCRIPTION (provided by applicant): New therapies are urgently needed for Acute Myelogenous Leukemia (AML). Treatment-resistant AML cells are evidently protected within bone marrow endosteal niches. This proposal is designed to provide groundwork for the development of new therapies aimed at inhibiting the cellular mechanisms of the bone marrow microenvironment that protect AML cells. We recently found that differentiating osteoblasts, but not the osteoprogenitors or terminally-differentiated osteocytes, are capable of protecting AML cells from apoptosis including that induced by SDF-1 (CXCL12) secreted by other cells in the bone marrow microenvironment. Additionally, our preliminary data indicates that differentiating osteoblasts also protect AML cells from chemotherapeutic-induced apoptosis. Interestingly, our results indicate that an early stage of differentiation of osteoprogenitors towards osteoblasts is crucial to permit these cells to protect AML cells. Inhibition of the specific stage(s) of osteoblat differentiation capable of protecting AML cells from SDF-1- or chemotherapeutic-induced apoptosis might enhance the efficacy of current therapies of AML. Unfortunately, this "protective" stage of osteoblast differentiation is not clearly defined at present. Here, we propos to use our in vitro co-culture systems and mouse models of AML to test our hypothesis that inhibiting osteoblast differentiation will significantly impair the ability of the endosteal bone marrow niche to protect AML cells. Our Aims are to 1) Disrupt specific stages of osteoblast differentiation via characterized genetic alterations in order to identify the particular stage(s) f osteoblast development capable of protecting AML cells in in vitro co-culture models of the bone marrow, and to 2) Determine the survival rate and localization of AML cells in mouse bone marrow microenvironments deficient in osteoblast differentiation, and assess the effects on the severity of AML disease and the rate of relapse in these animals. Combined, these studies will test our hypothesis and identify the particular stage(s) of osteoblast differentiation that mediate protection of AML cells from SDF-1- and chemotherapeutic-induced apoptosis.