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.
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.
Display omitted
•Upregulated FLT3, PDGFRβ, EGFR activate of MAPK pathway in the HSPC of MDS bone marrow resulting in abnormal hyper-proliferation.•ERK upregulate protein c-Myc and dephosphorylate Rb ...for easy cell cycle progression.•Premature apoptosis takes place through JNK pathway via c-Jun in Myelodysplastic HSPC’s.•The bone marrow hematopoietic stem cell expressing CD150 are hyperproliferative.•Simultaneously we can see a downregualtion of hematopoietic progenitor cells expressing CD90.
Myelodysplastic syndrome is considered globally as heterogenous group of neoplasm which often proclaims leukemic progression. The heterogeneity is reflected not only in clinical manifestations of the disease but also in salient causes of disease development. In spite of multiple therapeutic modalities, shortfall towards treatment of this disorder still persists. The focal point of tussle suggested toward defects, which are not confined to any unifying cellular signalling. The pathobiology of the disease often experiences an intriguing paradox involving ‘hyperproliferative bone marrow with pancytopenic peripheral blood’. In our present study we have reported about MAPK signaling in the hematopoietic stem progenitor compartmental (HSPC) dysregulation during the course of alkylator(ENU) induced myelodysplasia. The phospho-protein status of RTK’s(FLT3, PDGFR, EGFR) were markedly increased that activated MAPK signaling proteins which finally executed their tasks by transcription of c-Myc and Rb leading to uncontrolled cellular proliferation, simultaneously the activated c-Jun revealed stress related apoptosis. Altogether, the role of activated MAPK signaling in the HSPC’s may have led to hyperproliferation and concurrent enhanced apoptosis of abnormal cells which gradually headed towards premalignant transformations during the course of disease. The phenotypic expression of the HSPC markers CD 150 and CD 90 also established a mechanistic correlation with MAPK signalling alterations and overall scenario.
Hematological disorders like myelodysplastic syndrome (MDS) may arise due to cumulative dysregulation of various signalling pathways controlling proliferation, differentiation, maturation and ...apoptosis of bone marrow cells. This devastating bone marrow condition can be due to consequential abnormalities in haematopoiesis as well as its supportive microenvironment. Although mutations related to JAK/STAT pathway are common in myeloproliferative neoplasms, further studies are required to fully explore the myelodysplastic scenario regarding the concerned pathway. In this study, we have investigated the JAK-STAT signalling pathway which inevitably plays a crucial role in haematopoiesis. MDS was mimicked in a mouse model with an induction of ENU in adult mice. The bone marrow of the control and MDS groups of animals were subjected to a variety of tests, including cell morphology study in peripheral blood and bone marrow, cytochemistry and histochemistry of bone marrow smears, karyotyping and flowcytometric expression analysis of the phosphorylated forms of proteins like JAK1, STAT3 and STAT5 (denoted as pJAK1, pSTAT3 and pSTAT5) and the phenotypic expression of proteins like CD45 and CD71. The results revealed that the morphology of the blood and bone marrow cells were dysplastic compared to the affected blast populations of different lineages. The expression of common leucocyte antigen CD45 was less in comparison to the expression of transferrin receptor CD71 which was increased in the ENU induced MDS mouse model. Moreover, we have observed an upregulated expression of JAK1 followed by STAT5. Therefore, we can conclude that downregulation of CD45 may have helped in the upregulation of JAK-STAT signaling and CD71 expression. This aberrant signaling may be among one of the activated signaling axes that lead to affected hematopoietic lineages in Myelodysplastic syndrome.
Display omitted
•Lower CD45 level was associated with increased JAK1/STAT5 signalling in MDS marrow.•JAK1/STAT5 up-regulation may be linked to dysregulated haematopoiesis.•STAT5 up-regulation was associated with increased CD71 and erythroid dysplasia.
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.
