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Chem Biol Interact. 2017 Aug 1;273:1-10. doi: 10.1016/j.cbi.2017.05.014. Epub 2017 May 23.

Hematopathological alterations of major tumor suppressor cascade, vital cell cycle inhibitors and hematopoietic niche components in experimental myelodysplasia.

Author information

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.
2
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. Electronic address: msuj2002@yahoo.co.in.

Abstract

Myelodysplastic syndrome (MDS) is a poorly understood dreadful hematopoietic disorder that involves maturational defect and abnormalities in blood cell production leading to dysplastic changes and peripheral blood pancytopenia. The present work aims in establishing the mechanistic relationship of the expressional alterations of major tumor suppressor cascade, vital cell cycle inhibitors and hematopoietic microenvironmental components with the disease pathophysiologies. The study involves the development of N-N' Ethylnitrosourea (ENU) induced mouse model of MDS, characterization of the disease with blood film and bone marrow smear studies, scanning electron microscopic observation, mitochondrial membrane potential determination, flowcytometric analysis of osteoblastic and vascular niche components along with the expressional study of cleaved caspase-3, PCNA, Chk-2, p53, Ndn, Gfi-1, Tie-2, Sdf-1, Gsk-3β, p18 and Myt-1 in the bone marrow compartment. Dysplastic features were found in peripheral blood of MDS mice which seemed to be the consequence of three marrow pathophysiological conditions viz; aberrant rise of cellular proliferation, increased apoptosis and crowding of abnormal blast population. Expressional decline of the p53 cascade involving Chk-2, p53, Ndn, Gfi-1 along with the downregulation of major cell cycle inhibitors seemed to be associated with the hyper-proliferative nature of bone marrow cells during MDS. Moreover the disruption of osteoblastic niche components added to the decreased hematopoietic quiescency. Increased marrow vascular niche components signified the pre-malignant state of MDS. Elevated cellular apoptosis and rise in the blast burden were also found to be associated with the p53 expression dependent collapsing of mitochondrial membrane potential and upregulation of Tie-2 respectively. The study established the mechanistic correlation between the alterations of the mentioned signaling components and hematopoietic anomalies during MDS which may be beneficial for the development of therapeutic strategies for the disease.

KEYWORDS:

Apoptosis; Cell cycle; Hematopoiesis; Myelodysplastic syndrome; Niche

PMID:
28549617
DOI:
10.1016/j.cbi.2017.05.014
[Indexed for MEDLINE]

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