The functional interplay of transcription factors and cell adhesion molecules in experimental myelodysplasia including h
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The functional interplay of transcription factors and cell adhesion molecules in experimental myelodysplasia including hematopoietic stem progenitor compartment Suchismita Daw1 · Sujata Law1 Received: 19 June 2020 / Accepted: 19 September 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Myelodysplastic syndrome is a heterogenous group of disorder with clonal dysregulated hematopoiesis characterized by bone marrow failure, cytogenetic and molecular abnormalities and variable risk of progression to acute myeloid leukemia (AML). The bone marrow niche plays a major role in maintaining the homeostasis and is often injured by the chemotherapeutic drugs leading to catastrophic consequences like myelodysplastic syndrome. In the present study, we made an attempt to find out the osteoblastic niche related alterations in the myelodysplastic bone marrow through mainly flowcytometric and fluorescent microscopic studies. We have also checked the condition of the myelodysplastic bone through micro computed tomography. The results revealed that the affected osteoblasts of the myelodysplastic bone marrow compelled the hematopoietic stem cell to come out of quiescence and become actively proliferating, and in this scenario the decline in expression of cell adhesion molecules like N-Cadherin, Intercellular adhesion molecule 1 (ICAM) and upregulated focal adhesion kinase (FAK) played a major role. The hike in number of osteoclasts in myelodysplastic cases than control also shattered the balance between bone formation and resorption ratio. We have recorded a dysregulated expression of transcription factors GATA2 and CEBPα (CCAAT-enhancer-binding-protein) in the hematopoietic stem progenitor compartment of the myelodysplastic bone marrow, the main reason behind the presence of abnormal myeloblasts in myelodysplastic cases. Collectively, we can say the coordinated perturbations in the osteoblastic niche, cell adhesion molecules together with the transcription factors has resulted in the uncontrolled proliferation of hematopoietic stem cell, dysregulated myelopoiesis, early trafficking of hematopoietic progenitors to blood compartment and at the same time pancytopenic peripheral blood conditions during the progression of N-Ethyl N Nitroso Urea (ENU) induced myelodysplasia. Keywords MDS · Osteoblastic niche · Cell adhesion molecules · N-cadherin · CEBPα · GATA2 Abbreviations AML Acute myeloid leukemia ASXL1 Additional sex combs like-1 CAM Cell adhesion molecule CEBPα CCAAT-enhancer-binding-protein α E-Cadherin Epithelial cadherin ENU N-Ethyl N nitroso urea FAK Focal adhesion kinase HSC Hematopoietic stem cell HPC Hematopoietic progenitor cell
HSPC Hematopoietic stem progenitor compartment ICAM Intercellular adhesion molecule 1 N-Cadherin Neural cadherin PU1 Purine rich RANK Receptor activator of nuclear factor kappa-B ligand RUNX Runt-related transcription factor TET2 Tet methylcytosine dioxygenase 2 TP53 Tumor protein p53 TPO Thrombopoietin
* Sujata Law [email protected] 1
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