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1.
Leuk Lymphoma ; 49(10): 1963-75, 2008 Oct.
Article in English | MEDLINE | ID: mdl-18949619

ABSTRACT

Myelodysplastic syndromes (MDS) are common causes of ineffective hematopoiesis and cytopenias in the elderly. Various myelosuppressive and proinflammatory cytokines have been implicated in the high rates of apoptosis and hematopoietic suppression seen in MDS. We have previously shown that p38 MAPK is overactivated in MDS hematopoietic progenitors, which led to current clinical studies of the selective p38alpha inhibitor, SCIO-469, in this disease. We now demonstrate that the myelosuppressive cytokines TNFalpha and IL-1beta are secreted by bone marrow (BM) cells in a p38 MAPK-dependent manner. Their secretion is stimulated by paracrine interactions between BM stromal and mononuclear cells and cytokine induction correlates with CD34+ stem cell apoptosis in an inflammation-simulated in vitro bone marrow microenvironment. Treatment with SCIO-469 inhibits TNF secretion in primary MDS bone marrow cells and protects cytogenetically normal progenitors from apoptosis ex vivo. Furthermore, p38 inhibition diminishes the expression of TNFalpha or IL-1beta-induced proinflammatory chemokines in BM stromal cells. These data indicate that p38 inhibition has anti-inflammatory effects on the bone marrow microenvironment that complements its cytoprotective effect on progenitor survival. These findings support clinical investigation of p38alpha as a potential therapeutic target in MDS and other related diseases characterised by inflammatory bone marrow failure.


Subject(s)
Bone Marrow/pathology , Inflammation Mediators/antagonists & inhibitors , Myelodysplastic Syndromes/pathology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aged , Cytokines/antagonists & inhibitors , Cytokines/biosynthesis , Humans , Indoles/pharmacology , Inflammation/etiology , Interleukin-1beta/metabolism , Myelodysplastic Syndromes/drug therapy , Paracrine Communication/drug effects , Protein Kinase Inhibitors/pharmacology , Tumor Necrosis Factor-alpha/metabolism
2.
PLoS One ; 3(8): e2965, 2008 Aug 13.
Article in English | MEDLINE | ID: mdl-18698424

ABSTRACT

Microarray-based studies of global gene expression (GE) have resulted in a large amount of data that can be mined for further insights into disease and physiology. Meta-analysis of these data is hampered by technical limitations due to many different platforms, gene annotations and probes used in different studies. We tested the feasibility of conducting a meta-analysis of GE studies to determine a transcriptional signature of hematopoietic progenitor and stem cells. Data from studies that used normal bone marrow-derived hematopoietic progenitors was integrated using both RefSeq and UniGene identifiers. We observed that in spite of variability introduced by experimental conditions and different microarray platforms, our meta-analytical approach can distinguish biologically distinct normal tissues by clustering them based on their cell of origin. When studied in terms of disease states, GE studies of leukemias and myelodysplasia progenitors tend to cluster with normal progenitors and remain distinct from other normal tissues, further validating the discriminatory power of this meta-analysis. Furthermore, analysis of 57 normal hematopoietic stem and progenitor cell GE samples was used to determine a gene expression signature characteristic of these cells. Genes that were most uniformly expressed in progenitors and at the same time differentially expressed when compared to other normal tissues were found to be involved in important biological processes such as cell cycle regulation and hematopoiesis. Validation studies using a different microarray platform demonstrated the enrichment of several genes such as SMARCE, Septin 6 and others not previously implicated in hematopoiesis. Most interestingly, alpha-integrin, the only common stemness gene discovered in a recent comparative murine analysis (Science 302(5644):393) was also enriched in our dataset, demonstrating the usefulness of this analytical approach.


Subject(s)
Gene Expression Profiling/methods , Gene Expression , Hematopoietic Stem Cells/physiology , Oligonucleotide Array Sequence Analysis , Antigens, CD/analysis , Bone Marrow Cells/physiology , Cells, Cultured/pathology , Cells, Cultured/physiology , Databases, Genetic , Female , Hematopoietic Stem Cells/cytology , Hematopoietic Stem Cells/pathology , Humans , Male , Meta-Analysis as Topic , Organ Specificity , Reference Values
3.
Blood ; 112(8): 3434-43, 2008 Oct 15.
Article in English | MEDLINE | ID: mdl-18474728

ABSTRACT

MDS is characterized by ineffective hematopoiesis that leads to peripheral cytopenias. Development of effective treatments has been impeded by limited insight into pathogenic pathways governing dysplastic growth of hematopoietic progenitors. We demonstrate that smad2, a downstream mediator of transforming growth factor-beta (TGF-beta) receptor I kinase (TBRI) activation, is constitutively activated in MDS bone marrow (BM) precursors and is overexpressed in gene expression profiles of MDS CD34(+) cells, providing direct evidence of overactivation of TGF-beta pathway in this disease. Suppression of the TGF-beta signaling by lentiviral shRNA-mediated down-regulation of TBRI leads to in vitro enhancement of hematopoiesis in MDS progenitors. Pharmacologic inhibition of TBRI (alk5) kinase by a small molecule inhibitor, SD-208, inhibits smad2 activation in hematopoietic progenitors, suppresses TGF-beta-mediated gene activation in BM stromal cells, and reverses TGF-beta-mediated cell-cycle arrest in BM CD34(+) cells. Furthermore, SD-208 treatment alleviates anemia and stimulates hematopoiesis in vivo in a novel murine model of bone marrow failure generated by constitutive hepatic expression of TGF-beta1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-beta signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.


Subject(s)
Hematopoiesis , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Aged , Aged, 80 and over , Animals , Antigens, CD34/biosynthesis , Bone Marrow/drug effects , Bone Marrow/pathology , Female , Humans , Lentivirus/genetics , Male , Mice , Mice, Transgenic , Middle Aged , Models, Biological , Protein Serine-Threonine Kinases/metabolism , Pteridines/pharmacology , Receptor, Transforming Growth Factor-beta Type I , Receptors, Transforming Growth Factor beta/metabolism
4.
J Interferon Cytokine Res ; 27(7): 543-52, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17651015

ABSTRACT

Transforming growth factor-beta (TGF-beta) is an important physiologic regulator of cell growth and differentiation. TGF-beta has been shown to inhibit the proliferation of quiescent hematopoietic stem cells and stimulate the differentiation of late progenitors to erythroid and myeloid cells. Insensitivity to TGF-beta is implicated in the pathogenesis of many myeloid and lymphoid neoplasms. Loss of extracellular TGF receptors and disruption of intracellular TGF-beta signaling by oncogenes is seen in a variety of malignant and premalignant states. TGF-beta can also affect tumor growth and survival by influencing the secretion of other growth factors and manipulation of the tumor microenvironment. Recent development of small molecule inhibitors of TGF-beta receptors and other signaling intermediaries may allow us to modulate TGF signaling for future therapeutic interventions in cancer.


Subject(s)
Hematopoiesis , Leukemia/metabolism , Lymphoma/metabolism , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/metabolism , Receptors, Transforming Growth Factor beta/metabolism , Transforming Growth Factor beta/metabolism , Animals , Apoptosis , Humans , Leukemia/blood , Leukemia/drug therapy , Lymphoma/blood , Lymphoma/drug therapy , Multiple Myeloma/blood , Multiple Myeloma/drug therapy , Multiple Myeloma/metabolism , Myelodysplastic Syndromes/blood , Receptors, Transforming Growth Factor beta/blood , Signal Transduction , Transforming Growth Factor beta/biosynthesis , Transforming Growth Factor beta/blood
5.
Blood ; 108(13): 4170-7, 2006 Dec 15.
Article in English | MEDLINE | ID: mdl-16940419

ABSTRACT

The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly observed in varied morphologic subtypes of low-risk MDS and correlates with enhanced apoptosis observed in MDS hematopoietic progenitors. Most importantly, pharmacologic inhibition of p38alpha by a novel small molecule inhibitor, SCIO-469, decreases apoptosis in MDS CD34+ progenitors and leads to dose-dependant increases in erythroid and myeloid colony formation. Down-regulation of the dominant p38alpha isoform by siRNA also leads to enhancement of hematopoiesis in MDS bone marrow progenitors in vitro. These data implicate p38 MAPK in the pathobiology of ineffective hematopoiesis in lowrisk MDS and provide a strong rationale for clinical investigation of SCIO-469 in MDS.


Subject(s)
Bone Marrow/enzymology , Hematopoiesis , Indoles/pharmacology , Myelodysplastic Syndromes/enzymology , Myeloid Progenitor Cells/enzymology , p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors , Aged , Aged, 80 and over , Apoptosis/drug effects , Bone Marrow/pathology , Down-Regulation/drug effects , Female , Gene Expression Regulation, Enzymologic/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Hematopoiesis/drug effects , Humans , Indoles/therapeutic use , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Male , Middle Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/pathology , Myeloid Progenitor Cells/pathology , Neoplastic Stem Cells/enzymology , Neoplastic Stem Cells/pathology , RNA, Small Interfering/genetics , RNA, Small Interfering/pharmacology , Risk Factors , Tumor Cells, Cultured , p38 Mitogen-Activated Protein Kinases/metabolism
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