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Deregulation of vital mitotic kinase–phosphatase signaling in hematopoietic stem/progenitor compartment leads to cellular catastrophe in experimental aplastic anemia

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Abstract

Aplastic anemia, the paradigm of bone marrow failure, is characterized by pancytopenic peripheral blood and hypoplastic bone marrow. Among various etiologies, inappropriate use of DNA alkylating drugs like cyclophosphamide and busulfan often causes the manifestation of the dreadful disease. Cell cycle impairment in marrow hematopoietic stem/progenitor compartment together with cellular apoptosis has been recognized as culpable factors behind aplastic pathophysiologies. However, the intricate molecular mechanisms remain unrevealed till date. In the present study, we have dealt with the mechanistic intervention of the disease by peripheral blood hemogram, bone marrow histopathology, cytopathology, hematopoietic kinetic study, scanning electron microscopy, DNA damage assessment and flowcytometric analysis of cellular proliferation and apoptosis in hematopoietic stem/progenitor cell (HSPC) rich marrow compartment using busulfan and cyclophosphamidemediated mouse model. To unveil the molecular mechanisms behind aplastic pathophysiology, we further investigated the role of some crucial mitotic and apoptotic regulators like Protein kinase-B (PKB), Gsk-3β, Cyclin-D1, PP2A, Cdc25c, Plk-1, Aurora kinase-A, Chk-1 regarding the hematopoietic catastrophe. Our observations revealed that the alteration of PKB-GSK-3β axis, Plk-1, and Aurora kinase-A expressions in HSPC compartment due to DNA damage response was associated with the proliferative impairment and apoptosis during aplastic anemia. The study established the correlation between the accumulation of DNA damage and alteration of the mentioned molecules in aplastic HSPCs that lead to the hematopoietic catastrophe. We anticipate that our findings will be beneficial for developing better therapeutic strategies for the dreadful disease concerned.

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Acknowledgments

We are thankful to the Director of Calcutta School of Tropical Medicine for her support in successful completion of the study and to the Department of Biotechnology, Government of West Bengal for the sponsorship (Sanction No.124 (A)-BT (Estt)/RD-3/12 dt.27.2.13). We are also thankful to the Director of Center for Research in Nanoscience and Nanotechnology for helping us with scanning electron microscopy 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

    Ritam Chatterjee, Sukalpa Chattopadhyay & Sujata Law

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  1. Ritam Chatterjee
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Chatterjee, R., Chattopadhyay, S. & Law, S. Deregulation of vital mitotic kinase–phosphatase signaling in hematopoietic stem/progenitor compartment leads to cellular catastrophe in experimental aplastic anemia. Mol Cell Biochem 422, 121–134 (2016). https://doi.org/10.1007/s11010-016-2811-1

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