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Tel Aviv, Israel

Megakaryocytopoiesis involves the commitment of hematopoietic stem cell, the proliferation and terminal differentiation of the megakaryocytic progenitors and maturation to platelet producing megakaryocytes (MK). MKs align adjacent to bone marrow vascular endothelial cells, and form proplatelets. Platelets are released, or sheared from the MK directly into the circulation from the tips of proplatelets which protrude into the vascular lumen. The regulation of megakaryocytopoiesis is mediated through multiple hematopoietic growth factors, chemokines and cellular interactions via signal transduction pathways and integrated transcription factors. The primary physiological growth factor that regulates megakaryocytopoiesis and platelet production is thrombopoietin. Circulating Levels of thrombopoietin (TPO) induce concentration-dependent proliferation and maturation of MK progenitors by binding to the c-Mpl receptor and signaling induction. Increased concentration of free TPO resulting from decreased platelet turnover rates enables the compensatory response of marrow MKs to drive amplified platelet production. C-MpL signaling is orchestrated by a complex cascade of signaling molecules inducing the action of specific transcription factors to drive MK proliferation and maturation. Newly developed thrombopoietic agents operating via c-Mpl receptor have now been proven useful in supporting platelet production in thrombocytopenic states. In this article, the authors review the regulation of megakaryocytopoiesis and platelet production in normal and disease states, and new approaches of thrombopoietic therapy. Source

Ellis M.H.,The Hematology Institute | Ellis M.H.,Tel Aviv University | Baraf L.,The Hematology Institute | Shaish A.,The Bert rassburger Lipid Center | And 6 more authors.
Experimental Hematology

Myelodysplastic syndromes (MDS) are clonal stem cell diseases of the bone marrow characterized by abnormalities in maturation of hematopoietic cells of all lineages. MDS patients frequently have lower lipids and high rates of apoptosis and p53 (TP53) expression. An association between the reduced lipids in MDS and the expression of lipid-related genes was sought. We further evaluated whether 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGcoAR) and low-density lipoprotein receptor (LDL-R) are regulated by TP53 in vivo and in vitro. Gene expression was measured using real-time reverse transcription polymerase chain reaction on RNA extracted from bone marrow and peripheral blood from eight newly diagnosed MDS patients and eight controls and from mice livers. Serum lipid profile was measured using colorimetric enzymatic procedures. Total- and LDL cholesterol were lower in MDS patients in comparison to controls (p = 0.04 and p = 0.01, respectively). HMGcoAR messenger RNA increased in peripheral blood and bone marrow of MDS patients compared to controls (p = 0.04 and p = 0.01, respectively). LDL-R messenger RNA was higher only in the peripheral blood of MDS patients (p = 0.05). Comparable results were obtained in vivo. The transcription of these genes correlates with TP53 activation as documented by p21 messenger RNA elevation, a surrogate for TP53 activation and by using TP53 temperature-sensitive cells treated with adriamycin. To conclude, an association between reduced lipids in MDS and expression of HMGcoAR and LDL-R genes was documented. The transcription of these genes can be regulated by TP53. © 2012 ISEH - Society for Hematology and Stem Cells. Source

Herishanu Y.,The Hematology Institute | Kay S.,The Hematology Institute | Sarid N.,The Hematology Institute | Kohan P.,The Hematology Institute | And 9 more authors.
Leukemia Research

Peripheral absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral AMC in 80 treatment naive patients with CLL. Measurement of AMC was based on direct morphological enumeration, due to our findings that complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was within normal limits, however the AMC range exceeded the values of healthy individuals. The AMC trichotomized patients into 3 distinct sub-groups with different characteristics and outcomes. High AMC patients were younger and had higher absolute lymphocytes count, while patients with low AMC had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroups, whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes. © 2013 Elsevier Ltd. Source

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