Molecular basis of the inhibitory effects of ATRA on osteoblast-induced MDS/AML

成骨细胞是调节造血的造血干细胞(HSC)生态位的重要组成部分。 最近，它们已成为血液病髓系发育的关键调节因子。 恶性肿瘤。我们发现成骨细胞中β-连环蛋白信号的一个单一激活突变是 足以导致MDS的发展，在小鼠中迅速进展为AML。这种疾病是 可移植，在细胞遗传学水平上以克隆进化为特征。激活的β-连环蛋白信号是 在38%的MDS和AML患者的成骨细胞中存在，表明这一途径可能持续发育不良 人类的造血和向MDS和AML的进展。我们的初步观察支持这一迹象。 并进一步提出了一种治疗这一特殊人群的新方法。在寻找潜在的 FDA批准的一种化合物，具有抑制β-连环蛋白的能力，我们遇到了全反式维甲酸 (ATRA)。ATRA用于治疗急性早幼粒细胞白血病，其作用机制依赖于 关于它将NCoR-HDACL复合体从RAR中分离出来并允许DNA转录和 未成熟白血病早幼粒细胞向成熟粒细胞的分化。然而，来自体外的报告 研究表明，全反式维甲酸还有另一个功能：它抑制β-连环蛋白的功能。我们已经发现，抑制 14例骨髓增生异常综合征/急性髓系白血病患者的β-连环蛋白信号转导与全反式维甲酸联合应用可改善其功能 血液学表型，稳定疾病状态和抑制β-连环蛋白活性。它还治疗了MDS和 预防白血病小鼠的急性髓系白血病成骨细胞表达结构性活性β-连环蛋白。基于这些 观察到，我们假设干扰小鼠模型和成骨细胞中的β-连环蛋白信号 成骨细胞中β-连环蛋白活性的骨髓增生异常综合征/急性髓系白血病患者通过药物治疗将有所改善 疾病结局。这可以用全反式维甲酸实现，它可能会在治疗该部分中找到新的用途 在骨髓增生异常综合征/急性髓系白血病患者中，成骨细胞中存在激活的β-连环蛋白。为了检验这一假设，我们将检验 全反式维甲酸是否抑制β-连环蛋白诱导的急性髓系白血病小鼠成骨细胞中β-连环蛋白的活化； 这种抑制是否独立于对HSCs的作用。我们还将剖析β-连环蛋白的分子机制 ATRA的抑制作用；并从细胞遗传学的角度验证ATRA抑制的意义和特异性 体外成骨细胞和异种移植模型中不同类型人β-连环蛋白激活的骨髓和急性髓系白血病 我们开发的目的是研究人类MDS/AML和基质细胞之间的相互作用。

Osteoblasts are critical components of the hematopoietic stem cell (HSC) niche that regulate hematopoiesis. More recently, they have emerged as critical regulators of the development of hematological myeloid malignancies. We showed that a single activating mutation in β-catenin signaling in osteoblasts is sufficient to lead to the development of MDS, rapidly progressing to AML in mice. The disease is transplantable and characterized by clonal evolution at the cytogenetic level. Activated β-catenin signaling is present in osteoblasts of 38% of MDS and AML patients suggesting that this pathway may sustain dysplastic hematopoiesis and progression to MDS and AML in humans. Our initial observations support this indication and further suggest a novel means for treating this particular population of patients. In search of a potential FDA-approved compound with the ability to inhibit β-catenin signaling we came across all-trans-retinoic acid (ATRA). ATRA is used in the treatment of acute promyelocytic leukemia where its mechanism of action relies on its ability to dissociate the NCOR-HDACL complex from RAR and allow DNA transcription and differentiation of the immature leukemic promyelocytes into mature granulocytes. However, reports from in vitro studies indicate that ATRA has another function: it inhibits β-catenin functions. We have found that inhibition of β-catenin signaling in 14 MDS/AML patients with active β-catenin in their osteoblasts with ATRA improved their hematologic phenotype, stabilized disease status and inhibited β-catenin activity. It also treated MDS and prevented AML in leukemic mice expressing constitutive active β-catenin in osteoblasts. Based on these observations, we hypothesize that interrupting β-catenin signaling in osteoblasts of mouse models and MDS/AML patients with active β-catenin in their osteoblasts by pharmacological means will improve disease outcome. This may be achieved with ATRA, which may find a new use in the treatment of the portion of MDS/AML patients with activated β-catenin in their osteoblasts. To test this hypothesis we will examine whether ATRA inhibits β-catenin-induced AML on a mouse model of activated β-catenin in osteoblasts; and whether this inhibition is independent of actions on HSCs. We will also dissect the molecular mechanism of β-catenin inhibition by ATRA; and, verify the significance and specificity of ATRA inhibition in cytogenetically different types of human MDS and AML with activated β-catenin in osteoblasts in vitro and in xenograft models we developed to examine interactions between human MDS/AML and stromal cells.