Unveiling the paradoxical nature of myelodysplastic syndromes (MDS): Why hypercellular marrow strongly favors accelerated apoptosis

2013 ◽  
Vol 91 (5) ◽  
pp. 303-308 ◽  
Author(s):  
Madhurima Das ◽  
Samaresh Chaudhuri ◽  
Sujata Law
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Cellular Proliferation ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Expression Patterns ◽  
Extrinsic Pathway ◽  
Apoptosis Pathway ◽  
P53 Expression

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.

Myelodysplastic syndromes/myeloproliferative overlap neoplasms

2020 ◽  
pp. 191-203
Author(s):  
Eric Padron ◽  
Tariq I. Mughal ◽  
David Sallman ◽  
Alan F. List
Keyword(s):  
Bone Marrow ◽  
Clinical Trials ◽  
Stem Cell ◽  
Myelodysplastic Syndromes ◽  
Peripheral Blood ◽  
Myeloproliferative Neoplasms ◽  
Bone Marrow Failure ◽  
Disease Outcomes ◽  
Genomic Landscape ◽  
Bone Marrow Dysplasia

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are haematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) that display a paradoxical bone marrow phenotype hallmarked by myeloid proliferation in the context of bone marrow dysplasia and ineffective haematopoiesis. The unfolding MDS/MPN genomic landscape has revealed numerous mutations in signalling genes, such as CBL, JAK2, NRAS, KRAS, CSF3R, and others involving the spliceosome complex. These observations suggest that comutation of genes involved in dysplasia and bone marrow failure along with those of cytokine receptor signalling may, in part, explain the dual MDS/MPN phenotype. The respective MDS/MPN diseases are identified by the type of myeloid subset which predominates in the peripheral blood. Currently there are no standard treatment recommendations for most patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic endpoints and standardized response criteria for clinical trials.

Determination of normal expression patterns of CD86, CD210a, CD261, CD262, CD264, CD358, and CD361 in peripheral blood and bone marrow cells by flow cytometry

2018 ◽  
Vol 194 ◽  
pp. 44-55 ◽  
Author(s):  
Renata Cristina Messores Rudolf-Oliveira ◽  
Mariangeles Auat ◽  
Chandra Chiappin Cardoso ◽  
Iris Mattos Santos-Pirath ◽  
Barbara Gil Lange ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
Peripheral Blood ◽  
Bone Marrow Cells ◽  
Expression Patterns ◽  
Normal Expression ◽  
Marrow Cells

Extensive apoptosis of bone marrow cells as evaluated by the in situ end-labelling (ISEL) technique may be the basis for ineffective haematopoiesis in patients with myelodysplastic syndromes

2009 ◽  
Vol 62 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Agapi Parcharidou ◽  
Azra Raza ◽  
Theofanis Economopoulos ◽  
Efstathios Papageorgiou ◽  
Dimitra Anagnostou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Cells ◽  
Marrow Cells

scholarly journals Adult Mice With Targeted Mutation of the Interleukin-11 Receptor (IL11Ra) Display Normal Hematopoiesis

Blood ◽  
1997 ◽  
Vol 90 (6) ◽  
pp. 2148-2159 ◽  
Author(s):  
Harshal H. Nandurkar ◽  
Lorraine Robb ◽  
David Tarlinton ◽  
Louise Barnett ◽  
Frank Köntgen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Bone Marrow Cells ◽  
White Blood Cells ◽  
Null Mutation ◽  
Wild Type ◽  
Normal Numbers ◽  
Interleukin 11 ◽  
Marrow Cells

Abstract Interleukin-11 (IL-11) is a pleiotropic growth factor with a prominent effect on megakaryopoiesis and thrombopoiesis. The receptor for IL-11 is a heterodimer of the signal transduction unit gp130 and a specific receptor component, the α-chain (IL-11Rα). Two genes potentially encode the IL-11Rα: the IL11Ra and IL11Ra2 genes. The IL11Ra gene is widely expressed in hematopoietic and other organs, whereas the IL11Ra2 gene is restricted to only some strains of mice and its expression is confined to testis, lymph node, and thymus. To investigate the essential actions mediated by the IL-11Rα, we have generated mice with a null mutation of IL11Ra (IL11Ra−/−) by gene targeting. Analysis of IL11Ra expression by Northern blot and reverse transcriptase-polymerase chain reaction, as well as the absence of response of IL11Ra−/− bone marrow cells to IL-11 in hematopoietic assays, further confirmed the null mutation. Compensatory expression of the IL11Ra2 in bone marrow cells was not detected. IL11Ra−/− mice were healthy with normal numbers of peripheral blood white blood cells, hematocrit, and platelets. Bone marrow and spleen contained normal numbers of cells of all hematopoietic lineages, including megakaryocytes. Clonal cultures did not identify any perturbation of granulocyte-macrophage (GM), erythroid, or megakaryocyte progenitors. The number of day-12 colony-forming unit-spleen progenitors were similar in wild-type and IL11Ra−/− mice. The kinetics of recovery of peripheral blood white blood cells, platelets, and bone marrow GM progenitors after treatment with 5-flurouracil were the same in IL11Ra−/− and wild-type mice. Acute hemolytic stress was induced by phenylhydrazine and resulted in a 50% decrease in hematocrit. The recovery of hematocrit was comparable in IL11Ra−/− and wild-type mice. These observations indicate that IL-11 receptor signalling is dispensable for adult hematopoiesis.

Expression of Toll-like receptor 9 in bone marrow cells of myelodysplastic syndromes is down-regulated during transformation to overt leukemia

2010 ◽  
Vol 88 (2) ◽  
pp. 293-298 ◽  
Author(s):  
Nobuo Kuninaka ◽  
Morito Kurata ◽  
Kouhei Yamamoto ◽  
Shiho Suzuki ◽  
Shigeaki Umeda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Cells ◽  
Toll Like Receptor ◽  
Overt Leukemia ◽  
Marrow Cells

scholarly journals Analysis of interferon-inducible genes in cells of chronic myeloid leukemia patients responsive or resistant to an interferon-alpha treatment

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2337-2342
Author(s):  
IM Clauss ◽  
B Vandenplas ◽  
MG Wathelet ◽  
C Dorval ◽  
A Delforge ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Interferon Alpha ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Healthy Controls ◽  
Ifn Alpha ◽  
Inducible Genes ◽  
Marrow Cells

Recombinant human interferon-alpha (IFN-alpha) can induce a hematologic remission in patients with chronic myeloid leukemia. However, some patients are resistant and others develop late resistance to the IFN- alpha treatment. To understand the molecular mechanism of this resistance, we have analyzed the expression of 10 IFN-inducible genes in the cells of three resistant patients, two responsive patients, and six healthy controls. Northern blot hybridizations showed that all the genes were induced in in vitro IFN-alpha treated peripheral blood cells of the patients and healthy controls. These genes were also inducible in peripheral blood and bone marrow cells of two out of two resistant patients administered an injection of IFN-alpha. We conclude that the resistance to the IFN-alpha treatment of the chronic myeloid leukemia patients we studied is not due to (1) the absence of induction of any of the 10 IFN-inducible genes we studied, including the low-molecular- weight 2′-5′oligoadenylate synthetase; (2) the presence of an antagonist of IFN-alpha in the peripheral blood or bone marrow cells; and (3) the presence of neutralizing anti-IFN-alpha antibodies.

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