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

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Principal Investigator: STAVROULA  KOUSTENI
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $324,966
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases

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.

Terms: <AML - Acute Myeloid Leukemia><ATRA><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Acute Promyelocytic Leukemia><Agreement><Anabolism><Beta Cadherin-Associated Protein><Beta-1 Catenin><Blood Precursor Cell><Blood granulocytic cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CUL-2><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical Trials><Clonal Evolution><Complex><Cytogenetics><Cytosolic Protein Tyrosine Phosphastase><DNA><DNA Recombination><Data><Deoxyribonucleic Acid><Development><Disease><Disease Outcome><Disorder><Dissociation><Dysmyelopoietic Syndromes><FDA approved><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Recombination><Genetic Transcription><Genetic defect><Goals><Granular Leukocytes><Granulocytic Leukemia><Granulocytic cell><HSC niche><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Human><In Vitro><Interruption><Intracellular Communication and Signaling><Mesenchymal Progenitor Cell><Mesenchymal Stem Cells><Mesenchymal progenitor><Mesenchymal stromal/stem cells><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modern Man><Molecular><Murine><Mus><Mutation><Myelocytic Leukemia><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelogenous Leukemia><Myeloid Disease><Myeloid Leukemia><Myeloid Leukemia, Acute, M3><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Non-Lymphoblastic Leukemia><Non-Lymphocytic Leukemia><Non-Receptor Type 11 Protein Tyrosine Phosphatase><Nonlymphoblastic Leukemia><Nonlymphocytic Leukemia><Osteoblasts><PRO2286><PTP Family Gene><PTP-2 enzyme><PTP2C><PTPN11><PTPN11 gene><PTPase><Pathway interactions><Patients><Phenotype><Phosphotyrosine Phosphatase><Phosphotyrosyl Protein Phosphatase><Population><Progranulocytic Leukemia><Protein Tyrosine Phosphatase><Protein Tyrosine Phosphatase 2C><Protein Tyrosine Phosphatase Gene><Protein-Tyrosine Phosphatase 2C><RNA Expression><Receptor Type PTP Gene><Recombination><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Reporting><Retinoic Acid><Retinoic Acid Receptor><Role><SHP2><SHP2 Phosphatase><SHPTP2><Schwachman-Diamond><Severities><Shp-2 tyrosine phosphatase><Shwachman-Diamond><Shwachman-Diamond syndrome><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Smoldering Leukemia><Specificity><Stromal Cells><Syndrome><Testing><Trans Vitamin A Acid><Transcription><Transplantation><Tretinoin><Tretinoinum><Tyrosine Phosphatase><Tyrosine Phosphatase SHP2><Tyrosyl Phosphoprotein Phosphatase><Vitamin A Acid><Xenograft Model><acute granulocytic leukemia><acute myeloid leukemia><all-trans-Retinoic Acid><all-trans-Vitamin A acid><beta catenin><biological signal transduction><biosynthesis><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood stem cell niche><blood-forming stem cell><bone cell><developmental><genome mutation><granulocyte><hematopoietic progenitor><hematopoietic stem cell niche><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><human disease><improved><mesenchymal stromal progenitor cells><mesenchymal-derived stem cells><miRNA><miRNAs><mouse model><murine model><myelodysplasia><myeloid granulocytic leukemia><myeloproliferative neoplasm><myelosis><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><osteoprogenitor><osteoprogenitor cell><pathway><patient population><pharmacologic><prevent><preventing><progenitor><promyelocytic leukemia><protein tyrosine phosphate phosphohydrolase><social role><trans-Retinoic Acid><transplant><xenograft transplant model><xenotransplant model><β-catenin>