title: Unveiling the paradoxical nature of myelodysplastic syndromes (MDS): why hypercellular marrow strongly favors accelerated apoptosis.
abstract: The pathogenesis of bone marrow failure in myelodysplastic syndromes (MDS) is an unresolved mystery. MDS causes peripheral blood cytopenias and increased bone marrow cellularity. This apparent paradox has been interpreted as a sign of intramedullary destruction of a substantial portion of the developing hematopoietic cells by apoptosis. The present study aimed to delineate the exact mechanistic relationship between the bone marrow hypercellularity and the accelerated apoptosis in an N-ethyl-N-nitrosourea (ENU)-induced experimental MDS mouse model. The observations made so far clarify the quantitative and qualitative changes that occur in the bone marrow microenvironment through cell cycle analysis, especially involving the telomerase reverse transcriptase (TERT) and p53 expression patterns. The survival fate of the bone marrow cells were observed by measuring the expression level of some intracellular protein molecules like apoptosis signal-regulating kinase 1 (ASK-1), c-Jun N-terminal kinase (JNK), and cleaved caspase-3 of the extrinsic pathway toward apoptosis. We found myelodysplasia damage occurs within one or more multipotent progenitor populations resulting in uncontrolled cellular proliferation within the MDS bone marrow. Then, due to homeostatic balance, this high cellular burden is minimized by activating the apoptosis pathway. As a result, the peripheral blood suffers cellular deprivation. This study can throw some light on the mechanism of disease progression and also help to reveal the paradoxical nature of the disease.
authors.affiliation: a Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, 108 C R Avenue, Kolkata, West Bengal, India, 700073.
authors.forename: Madhurima
authors.initials: M
authors.lastname: Das
authors.forename: Samaresh
authors.initials: S
authors.lastname: Chaudhuri
authors.forename: Sujata
authors.initials: S
authors.lastname: Law
mesh_terms: D000741:Anemia, Aplastic; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D005038:Ethylnitrosourea / Q000494:pharmacology; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000096:biosynthesis / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000096:biosynthesis / Q000378:metabolism; D008297:Male; D051379:Mice; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D019098:Telomerase / Q000096:biosynthesis / Q000378:metabolism; D059506:Telomere Shortening; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000378:metabolism; D019014:fas Receptor / Q000096:biosynthesis / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D016159:Tumor Suppressor Protein p53; D019014:fas Receptor; D048031:JNK Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse; D019098:Telomerase; D053148:Caspase 3; D005038:Ethylnitrosourea