Cellular and Molecular mechanisms of ATRA inhibition of osteoblast-induced MDS development

ATRA 抑制成骨细胞诱导的 MDS 发展的细胞和分子机制

基本信息

批准号：
10348733
负责人：
STAVROULA KOUSTENI
金额：
$ 33.17万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-15 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10348733
关键词：
Acute Myelocytic Leukemia Acute Promyelocytic Leukemia Agreement Anabolism Bone Marrow Cells Clinical Trials Clonal Evolution Complex Cytogenetics DNA Data Development Diamond Disease Disease Outcome Dysmyelopoietic Syndromes FDA approved Genetic Recombination Genetic Transcription Goals Hematology Hematopoiesis Hematopoietic Hematopoietic stem cells Human In Vitro Interruption Lead Mesenchymal MicroRNAs Molecular Mus Mutation Myeloproliferative disease Osteoblasts PTPN11 gene Pathway interactions Patients Pharmacology Phenotype Population Progranulocytes Protein Tyrosine Phosphatase Reporting Retinoic Acid Receptor Role Severities Signal Pathway Signal Transduction Specificity Stromal Cells Syndrome Testing Transplantation Tretinoin Xenograft Model base beta catenin bone cell granulocyte hematopoietic stem cell niche human disease improved leukemia mouse model novel novel therapeutic intervention osteoprogenitor cell patient population prevent progenitor stem stem cells

项目摘要

ABSTRACT 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 -catenin signaling in osteoblasts is sufficient to lead to the development of MDS, eventuall progressing to AML in mice. The disease is transplantable and characterized by clonal evolution at the cytogenetic level. Activated -catenin signaling is present in osteoblasts of 38% of MDS 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 -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 -catenin functions. We have found that inhibition of -catenin signaling in 14 MDS/ patients with active -catenin in their osteoblasts with ATRA improved their hematologic phenotype, stabilized disease status and inhibited -catenin activity. It also treated MDS and prevented disease transformation in MDS mice expressing constitutive active -catenin in osteoblasts. Based on these observations, we hypothesize that interrupting -catenin signaling in osteoblasts of MDS mouse models and MDS patients with active -catenin in their osteoblasts by pharmacological means will improve disease outcome. This may be achieved with ATRA, which may find a new use specifically in the treatment of the portion of MDS patients with activated -catenin in their osteoblasts. To test this hypothesis we will examine whether ATRA inhibits -catenin-induced MDS in mouse models of activated -catenin in osteoblasts; and whether this inhibition is independent of actions on HSCs. We will also dissect the molecular mechanism of -catenin inhibition by ATRA; and, verify the significance and specificity of ATRA inhibition in cytogenetically different types of human MDS with activated -catenin in osteoblasts in vitro and in xenograft models we developed to examine interactions between human MDS and stromal cells.

抽象的成骨细胞是调节造血功能的造血干细胞（HSC）生态位的关键组成部分。最近，它们已成为血液骨髓细胞发育的关键调节因子。我们发现成骨细胞中 -连环蛋白信号传导的单一激活突变是足以导致 MDS 的发展，并最终发展为小鼠的 AML。可移植并以细胞遗传学水平的克隆进化为特征。存在于 38% MDS 患者的成骨细胞中，表明该途径可能维持发育不良我们的初步观察结果支持这一迹象。并进一步提出治疗这一特定患者群体的新方法。 FDA 批准的化合物能够抑制 -连环蛋白信号传导，我们遇到了全反式视黄酸（ATRA）用于治疗急性早幼粒细胞白血病，其作用机制依赖于其将 NCOR-HDACL 复合物与 RAR 分离并允许 DNA 转录和然而，来自体外的报告表明，未成熟的白血病早幼粒细胞分化为成熟的粒细胞。研究表明ATRA还有另一个功能：它抑制-连环蛋白的功能。我们发现抑制作用。 14 名 MDS/成骨细胞中含有活性 β-连环蛋白的患者中，使用 ATRA 后，-连环蛋白信号传导改善了他们的它还治疗MDS和血液学表型，稳定疾病状态并抑制β-连环蛋白活性。在成骨细胞中表达组成型活性 β-连环蛋白的 MDS 中，可预防疾病转化。根据这些观察结果，我们发现干扰 MDS 小鼠成骨细胞中的 β-连环蛋白信号传导通过药理学手段，模型和 MDS 患者的成骨细胞中含有活性 β-连环蛋白，这可以通过 ATRA 来实现，它可能会在特定领域找到新的用途。对部分MDS患者的成骨细胞中激活的β-连环蛋白进行治疗以检验这一假设。我们将在激活 β-catenin 的小鼠模型中检查 ATRA 是否抑制 β-catenin 诱导的 MDS 成骨细胞；以及这种抑制是否独立于 HSC 的作用。我们还将剖析该分子。 ATRA 抑制 -catenin 的机制；并验证 ATRA 抑制的意义和特异性体外成骨细胞和异种移植物中具有激活的β-连环蛋白的细胞遗传学不同类型的人类MDS 我们开发的模型用于检查人类 MDS 和基质细胞之间的相互作用。