March 9th, 2010 / No Comments » / by Challen GA, Goodell MA
Runx1 Isoforms Show Differential Expression Patterns During Hematopoietic Development But Have Similar Functional Effects in Adult Hematopoietic Stem Cells.
Exp Hematol. 2010 Mar 2;
Authors: Challen GA, Goodell MA
OBJECTIVE: RUNX1/AML1 is an essential regulator of hematopoiesis and has multiple isoforms arising from differential splicing and utilization of two promoters. We hypothesized that the rare Runx1c isoform has a distinct role in hematopoietic stem cells (HSCs). METHODS: We have characterized the expression pattern of Runx1c in mouse embryos and human embryonic stem cell (hESC)-derived embryoid bodies using in situ hybridization, and expression levels in mouse and human HSCs by real-time PCR. We then determined the functional effects of Runx1c using enforced retroviral over-expression in mouse HSCs. RESULTS: We observed differential expression profiles of RUNX1 isoforms during hematopoietic differentiation of hESCs. The RUNX1a and RUNX1b isoforms were expressed consistently throughout hematopoietic differentiation whereas the RUNX1c isoform was only expressed at the time of emergence of definitive HSCs. RUNX1c was also expressed in the AGM region of E10.5-11.5 mouse embryos, the region where definitive HSCs arise. These observations suggested that the RUNX1c isoform may be important for the specification or function of definitive HSCs. However, using retroviral over-expression to study the effect of RUNX1 isoforms on HSCs in a gain-of-function system, no discernable functional difference could be identified between RUNX1 isoforms in mouse HSCs. Over-expression of both RUNX1b and RUNX1c induced quiescence in mouse HSCs in vitro and in vivo. CONCLUSIONS: Although the divergent expression profiles of Runx1 isoforms during development suggest specific roles for these proteins at different stages of HSC maturation, we could not detect an important functional distinction in adult mouse HSCs using our assay systems.
PMID: 20206228 [PubMed - as supplied by publisher]
Posted in: Exp Hematol
March 9th, 2010 / No Comments » / by Sercan Z, Pehlivan M, Sercan HO
Expression profile of WNT, FZD and sFRP genes in human hematopoietic cells.
Leuk Res. 2010 Mar 4;
Authors: Sercan Z, Pehlivan M, Sercan HO
Identifying gene expression differences in the Wnt signaling pathway specific to leukemic cells can be hampered by the lack of verified knowledge on the expression of WNT genes in normal blood cells. In this study we aimed to determine the expression profile of human WNT, FZD and sFRP genes in normal adult bone marrow, T and B cells; along with the hematopoietic cell lines K562, HL60, Jurkat and Namalwa. Bone marrow and peripheral blood from 16 donors were evaluated and our results were compared with the GeneNote database expression arrays. In bone marrow, only WNT3, WNT10A, FZD3, FZD7 and sFRP1 genes are constitutively expressed. Lymphocytes express WNT7A, WNT9B, FZD6 and FZD7 in addition to the genes above, but T cells differ in that they lose sFRP1 expression and gain constitutive expression of WNT16. An established "normal" profile of the Wnt genes in various blood cells will provide a fundamental basis for research investigating hematopoiesis and cellular processes during leukemic transformation.
PMID: 20206998 [PubMed - as supplied by publisher]
Posted in: Leuk Res
March 9th, 2010 / No Comments » / by Baron M, Bachmeyer C, Khalil A, Hagège I, Lionnet F
[Sacral extramedullary hematopoiesis in a patient with thalassemia.]
Presse Med. 2010 Mar 4;
Authors: Baron M, Bachmeyer C, Khalil A, Hagège I, Lionnet F
PMID: 20207101 [PubMed - as supplied by publisher]
Posted in: Presse Med
March 9th, 2010 / No Comments » / by Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S
Endothelial Cells Are Essential for the Self-Renewal and Repopulation of Notch-Dependent Hematopoietic Stem Cells.
Cell Stem Cell. 2010 Mar 5;6(3):251-264
Authors: Butler JM, Nolan DJ, Vertes EL, Varnum-Finney B, Kobayashi H, Hooper AT, Seandel M, Shido K, White IA, Kobayashi M, Witte L, May C, Shawber C, Kimura Y, Kitajewski J, Rosenwaks Z, Bernstein ID, Rafii S
Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long-term hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free cocultures, ECs, through direct cellular contact, stimulated incremental expansion of repopulating CD34(-)Flt3(-)cKit(+)Lineage(-)Sca1(+) LT-HSCs, which retained their self-renewal ability, as determined by single-cell and serial transplantation assays. Angiocrine expression of Notch ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2-deficient, mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp(+) LT-HSCs were detected in cellular contact with sinusoidal ECs. Interference with angiocrine, but not perfusion, function of SECs impaired repopulation of TNR.Gfp(+) LT-HSCs. ECs establish an instructive vascular niche for clinical-scale expansion of LT-HSCs and a cellular platform to identify stem cell-active trophogens.
PMID: 20207228 [PubMed - as supplied by publisher]
Posted in: Cell Stem Cell
March 9th, 2010 / No Comments » / by Challen GA, Boles NC, Chambers SM, Goodell MA
Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGF-beta1.
Cell Stem Cell. 2010 Mar 5;6(3):265-278
Authors: Challen GA, Boles NC, Chambers SM, Goodell MA
The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased HSCs (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers. These phenotypes are stable under natural (aging) or artificial (serial transplantation) stress and are exacerbated in the presence of competing HSCs. My- and Ly-HSCs respond differently to TGF-beta1, presenting a possible mechanism for differential regulation of HSC subtype activation. This study demonstrates definitive isolation of lineage-biased HSC subtypes and contributes to the fundamental change in view that the hematopoietic system is maintained by a continuum of HSC subtypes, rather than a functionally uniform pool. PAPERFLICK:
PMID: 20207229 [PubMed - as supplied by publisher]
Posted in: Cell Stem Cell
March 9th, 2010 / No Comments » / by Sweeney E, Roberts D, Corbo T, Jacenko O
Congenic Mice Confirm That Collagen X Is Required for Proper Hematopoietic Development.
PLoS One. 2010;5(3):e9518
Authors: Sweeney E, Roberts D, Corbo T, Jacenko O
The link between endochondral skeletal development and hematopoiesis in the marrow was established in the collagen X transgenic (Tg) and null (KO) mice. Disrupted function of collagen X, a major hypertrophic cartilage matrix protein, resulted in skeletal and hematopoietic defects in endochondrally derived tissues. Manifestation of the disease phenotype was variable, ranging from perinatal lethality in a subset of mice, to altered lymphopoiesis and impaired immunity in the surviving mice. To exclude contribution of strain specific modifiers to this variable manifestation of the skeleto-hematopoietic phenotype, C57Bl/6 and DBA/2J collagen X congenic lines were established. Comparable disease manifestations confirmed that the skeleto-hematopoietic alterations are an inherent outcome of disrupted collagen X function. Further, colony forming cell assays, complete blood count analysis, serum antibody ELISA, and organ outgrowth studies established altered lymphopoiesis in all collagen X Tg and KO mice and implicated opportunistic infection as a contributor to the severe disease phenotype. These data support a model where endochondral ossification-specific collagen X contributes to the establishment of a hematopoietic niche at the chondro-osseous junction.
PMID: 20209091 [PubMed - as supplied by publisher]
Posted in: PLoS One
March 9th, 2010 / No Comments » / by pubmed
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Posted in: Report
March 6th, 2010 / No Comments » / by Konopleva M, Tabe Y, Zeng Z, Andreeff M
Therapeutic targeting of microenvironmental interactions in leukemia: mechanisms and approaches.
Drug Resist Updat. 2009 Aug-Oct;12(4-5):103-13
Authors: Konopleva M, Tabe Y, Zeng Z, Andreeff M
In hematological malignancies, there are dynamic interactions between leukemic cells and cells of the bone marrow microenvironment. Specific niches within the bone marrow microenvironment provide a sanctuary for subpopulations of leukemic cells to evade chemotherapy-induced death and allow acquisition of a drug-resistant phenotype. This review focuses on molecular and cellular biology of the normal hematopoietic stem cell and the leukemia stem cell niche, and of the molecular pathways critical for microenvironment/leukemia interactions. The key emerging therapeutic targets include chemokine receptors (CXCR4), adhesion molecules (VLA4 and CD44), and hypoxia-related proteins HIF-1alpha and VEGF. Finally, the genetic and epigenetic abnormalities of leukemia-associated stroma will be discussed. This complex interplay provides a rationale for appropriately tailored molecular therapies targeting not only leukemic cells but also their microenvironment to ensure improved outcomes in leukemia.
PMID: 19632887 [PubMed - indexed for MEDLINE]
Posted in: Drug Resist Updat
March 6th, 2010 / No Comments » / by Ozkurt ZN, YaÄŸci M, Sucak GT, Kirazli S, Haznedar R
Thrombopoietic cytokines and platelet count in multiple myeloma.
Platelets. 2010 Feb;21(1):33-6
Authors: Ozkurt ZN, Yağci M, Sucak GT, Kirazli S, Haznedar R
Cytokines like interleukin (IL)-6 and IL-1beta are both implicated in multiple myeloma (MM) pathogenesis and megakaryopoiesis. The dynamic interaction between thrombopoiesis and thrombopoietic cytokines in MM may affect platelet (PLT) counts. Sixty-eight patients with MM (30 female, 38 male; median age 58 (40-79), 38 newly diagnosed, 15 in plateau, and 15 relapse and/or refractory patients) and 21 controls were included in the study. Plasma levels of thrombopoietin (TPO), IL-1beta, IL-11 and IL-6 were measured by ELISA. PLT counts were not different between the control group and MM patients with various disease stages and activity. IL-6 and TPO levels were higher in MM patients than healthy subjects (p < 0.001). PLT counts were inversely correlated with TPO (r = -0.566; p < 0.001) and positively correlated with IL-6 (r = 0.263; p = 0.04) levels in MM patients. TPO and IL-6 levels were significantly correlated (r = 0.305; p < 0.001). Disease activity has no effect on plasma cytokine levels. TPO levels were higher in stage III than stage I (p = 0.05) and stage II (p = 0.03) patients in newly diagnosed MM. High TPO levels induced by IL-6 may sustain normal PLT counts despite bone marrow infiltration by plasma cells and decreased PLT half-life.
PMID: 19891528 [PubMed - indexed for MEDLINE]
Posted in: Platelets
March 6th, 2010 / No Comments » / by Goldberg ED, Dygai AM, Skurikhin EG, Pershina OV, Minakova MY, Ermakova NN, Firsova TV
Potentiation of the stimulatory effect of erythropoietin on erythropoiesis by antiserotonin drug during cytostatic myelosuppression.
Bull Exp Biol Med. 2009 Jul;148(1):45-8
Authors: Goldberg ED, Dygai AM, Skurikhin EG, Pershina OV, Minakova MY, Ermakova NN, Firsova TV
Combined stimulatory effect of antiserotonin drug and erythropoietin on the bone marrow erythropoiesis was studied under conditions of cytostatic myelosuppression. The stimulatory effect of erythropoietin on regeneration of the hemopoietic erythroid stem increased, if serotonin mediation in the CNS was disordered before induction of cytostatic myelosuppression. The stimulatory effect of a combination of cyproheptadine and epocrine (experimental group) significantly surpassed that of cyproheptadine and epocrine monotherapies. The increase in the content of erythroid elements in the blood system of experimental animals was due to recovery of the structural and functional integrity of the hemopoietic tissue (at the expense of reduction of the suppressive effect of CNS serotonin on the formation of erythroid hemopoietic islets) and simultaneous stimulation of division and maturation of erythroid precursors with epocrine.
PMID: 19902094 [PubMed - indexed for MEDLINE]
Posted in: Bull Exp Biol Med
