The conversion of physiology to pathophysiology in hematological disorders viz: aplastic anemia, myelodysplastic syndrome (MDS) and leukemia in murine models was the subject of study in the present programme. Peripheral blood hemogram, spleno-somatic index, bone marrow smear study, cytochemical staining of marrow, cell release kinetics study during marrow explants culture, hematopoietic niche assessment, chromosomal aberration study, plasma membrane stability study of marrow cells, lysosomal membrane and mitochondrial membrane stability study and innate immune parameters were performed in the aplastic anemia, leukemia and MDS mouse model. In bone marrow aplasia, peripheral blood pancytopenia, marrow hypocellularity, decreased marrow cellular viability, deterioration of bone marrow hematopoiesis as well as hematopoietic microenvironment and extramedullary hematopoiesis were noticed. In addition, disruption of mitochondrial and lysosomal membrane integrity along with reduction of innate immune parameters were found in the hematopoietic suppressed condition. Surprisingly, no noticeable chromosomal aberration was found in the aplastic condition. Ineffective marrow hematopoiesis together with the disruption of hematopoietic microenvironment was observed in MDS. Also, extramedullary hematopoiesis, increased marrow cellular death, chromosomal aberration and loss of innate immunity were the common events. During leukemia, the number of functionally and structurally immature cells in the peripheral blood and bone marrow was increased together with malignant conversion of hematopoietic cells in the presence of malignancy supportive stromal microenvironment. Chromosomal aberration, decrease of cell mediated immunity with least mitochondrial apoptotic damage were also found in leukemic condition as well.
Myelodysplastic syndrome (MDS) is regarded as a spectrum of bone marrow failure disorders that share hemato‐pathological state of cellular dysplasia and cytopenia. The modern treatment of cancers like chemotherapy and radiation therapy sometimes severely pounce on the basic hematopoietic stem/progenitor cellular (HSPC) compartment which gradually disclose the clinical symptoms of MDS. The present study involves flowcytometric protein expression analysis of insulin growth factor receptor (IGFR), PI3K‐Akt‐mTOR pathway, the autophagy related proteins (ATG's), the status of antioxidative molecules SOD2 and SDF1 and apoptosis profiling in ethyl‐nitroso‐urea induced myelodysplasia. The redox status that is, reactive oxygen species was estimated with dihydroetidium and the status of mitochondria and lysosomes were checked by Janus green B and neutral red staining respectively, pre and post quercetin treatment in MDS bone marrow. The results revealed the activated IGFR/PI3K/Akt axis in MDS bone marrow but unconventionally both p‐mTOR and autophagy (p‐ATG1, p‐AT6, ATG7, ATG12) was downregulated. Interestingly, post quercetin treatment an upregulation of basal autophagocytosis, reversal of oxidative damage and proper functionality of mitochondria and lysosome was recorded. Taken together, the study hinted that the PI3K‐Akt‐mTOR pathway does not rule over the process of autophagocytosis in HSPC's of MDS bone marrow and the isoflavanoid quercetin remarkably restored autophagocytosis and hematopoietic oxidative status toward normalcy during the progression of myelodysplasia.
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