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

• 批准号: 10542398
• 负责人: STAVROULA KOUSTENI
• 金额: $ 33.5万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 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/10542398
• 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; Dissociation; Dysmyelopoietic Syndromes; FDA approved; Genetic Recombination; Genetic Transcription; Goals; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; In Vitro; Interruption; Mesenchymal Stem Cells; MicroRNAs; Molecular; Mus; Mutation; Myeloid Leukemia; Myeloproliferative disease; Osteoblasts; PTPN11 gene; Pathway interactions; Patients; Phenotype; Population; Protein Tyrosine Phosphatase; Reporting; Retinoic Acid Receptor; Role; Severities; Signal Induction; Signal Pathway; Signal Transduction; Specificity; Stromal Cells; Syndrome; Testing; Transplantation; Tretinoin; Xenograft Model; beta catenin; bone cell; granulocyte; hematopoietic stem cell niche; human disease; improved; mouse model; novel; novel therapeutic intervention; osteoprogenitor cell; patient population; pharmacologic; prevent; progenitor

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的造血干细胞（HSC）小裂的关键成分。 最近，它们已成为血液学髓样发展的关键调节剂 恶性肿瘤。我们表明，成骨细胞中的-catenin信号传导中的单个激活突变为 足以导致MD的发展，最终发展为小鼠的AML。疾病是 可移植和特征是细胞遗传学水平的克隆进化。激活的-catenin信号是 38％的MDS患者的成骨细胞中存在，这表明该途径可能维持不塑性 人类造血和向MDS和AML的进展。我们最初的观察支持此迹象 并进一步提出了一种新的手段来治疗这一特定患者人群。寻找潜力 FDA批准的化合物具有抑制-catenin信号传导的能力 （ATRA）。 ATRA用于治疗其作用机理的急性寄生虫细胞性白血病 关于其能够将NCOR-HDACL复合物与RAR分离并允许DNA转录和 未成熟的白血病叶虫细胞分化为成熟的颗粒细胞。但是，体外报告 研究表明ATRA具有另一个功能：它抑制-catenin的功能。我们发现抑制 -catenin信号在其成骨细胞中有14例MDS/活性-catenin的患者具有ATRA，可改善其 血液学表型，稳定的疾病状态和抑制 - 连环蛋白活性。它还治疗了MD和 防止在成骨细胞中表达构成活性-catenin的MDS小鼠的疾病转化。基于 在这些观察结果上，我们假设在MDS小鼠的成骨细胞中中断-catenin信号传导 模型和MDS患者在其成骨细胞中通过药物手段将 改善疾病结果。这可以通过ATRA实现，该ATRA可能会在 在其成骨细胞中的MDS患者的一部分治疗-catenin。检验这一假设 我们将检查ATRA是否在活化的-catenin的小鼠模型中抑制-catenin诱导的MD 成骨细胞；这种抑制是否与对HSC的行为无关。我们还将剖析分子 ATRA抑制 - 连续素的机制；并验证ATRA抑制的显着性和特异性 细胞遗传学上不同类型的人类MDS在体外和异种移植物中具有活化的-catenin的人类MD 我们开发的模型是为了检查人MDS与基质细胞之间的相互作用。