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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：
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
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/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

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.

摘要