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The functional interplay of transcription factors and cell adhesion molecules in experimental myelodysplasia including hematopoietic stem progenitor compartment

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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.

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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

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Acknowledgements

We are thankful to the Department of Biotechnology, Government of West Bengal for the financial assistance {Sanction No. 124 (A)-BT (Estt)/RD-3/12 dt.27.2.13} and Department of Science and Technology, Government of India, [No. DST/INSPIRE Fellowship/2015/IF150411] for their sponsorship. We are grateful to the Director of the Calcutta School of Tropical Medicine (Kolkata) for his encouragement and support for the successful completion of this work. Authors also acknowledge the Head of the Department of Biological Sciences, Presidency University for fluorescence microscopy facility, CRNN(Centre for Research in Nanoscience And Nanotechnology) for their electron microscopy facility and IIT Kharagpur, Central Research Facility for the Micro CT facility.

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  1. Stem Cell Research and Application Unit, Department of Biochemistry and Medical, Biotechnology, Calcutta School of Tropical Medicine, 108, C.R Avenue, Kolkata, 700073, West Bengal, India

    Suchismita Daw & Sujata Law

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Daw, S., Law, S. The functional interplay of transcription factors and cell adhesion molecules in experimental myelodysplasia including hematopoietic stem progenitor compartment. Mol Cell Biochem 476, 535–551 (2021). https://doi.org/10.1007/s11010-020-03920-6

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