scholarly journals Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors

Blood ◽  
2006 ◽  
Vol 108 (13) ◽  
pp. 4170-4177 ◽  
Author(s):  
Tony A. Navas ◽  
Mani Mohindru ◽  
Myka Estes ◽  
Jing Ying Ma ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
P38 Mapk ◽  
Myelodysplastic Syndromes ◽  
Clinical Investigation ◽  
P38 Map Kinase ◽  
Hematopoietic Progenitors ◽  
Molecule Inhibitor ◽  
Pharmacologic Inhibition

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 p38α 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 p38α 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.

Stimulation of Hematopoiesis by Amifostine in Patients With Myelodysplastic Syndrome

Blood ◽  
1997 ◽  
Vol 90 (9) ◽  
pp. 3364-3369 ◽  
Author(s):  
Alan F. List ◽  
Farah Brasfield ◽  
Ruth Heaton ◽  
Betty Glinsmann-Gibson ◽  
Linda Crook ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Dose Schedule ◽  
Treatment Withdrawal ◽  
Red Blood Cell Transfusion ◽  
Refractory Anemia ◽  
Hematopoietic Progenitors ◽  
Absolute Increase ◽  
Hematological Effects

Abstract The aminothiol, amifostine (Ethyol; U.S. Bioscience, West Conshohocken, PA), is a cytoprotective agent that ameliorates the toxicities of anticancer therapy. In vitro, amifostine promotes the formation and survival of primitive hematopoietic progenitors derived from myelodysplastic bone marrow (BM) specimens. To evaluate the hematological effects of amifostine, 18 patients with myelodysplastic syndrome (MDS) and one or more refractory cytopenias received treatment with amifostine in a Phase I/II study. Four cohorts received intravenous treatment with 100, 200, or 400 mg/m2 amifostine three times a week, or 740 mg/m2 weekly for three consecutive weeks followed by 2 weeks observation. Nonresponding patients received a second course of therapy at the next higher dose level depending upon drug tolerance. Bone marrow (BM) progenitor growth was assessed before treatment and after day 21. Diagnoses included refractory anemia (7), refractory anemia with ringed sideroblasts (5), refractory anemia with excess blasts (RAEB) (4), and RAEB-in transformation (RAEB-t) (2). Single- or multi-lineage hematologic responses occurred in 15 patients (83%) treated with the three-times-a-week dose schedule. Fourteen patients had a 50% or greater increase in absolute neutrophil count with amifostine treatment (range, 426 to 11,348/μL). Platelet count increased in 6 (43%) of 14 patients with thrombocytopenia (absolute increase, 16,000 to 110,000/μL), and 5 of 15 red blood cell transfusion-dependent patients had a 50% of greater reduction in transfusion needs. Assayable hematopoietic progenitors increased in 13 of 15 evaluable patients; including CFU-GEMM (12), BFU-E (8), and CFU-GM (6). Amifostine doses less than or equal to 200 mg/m2 were well tolerated, whereas grade II nausea, vomiting, and fatigue was limiting at higher doses. Three patients with excess blasts before enrollment experienced an increase in BM blast percentage and two patients had evolution to acute leukemia that persisted after treatment withdrawal. We conclude that amifostine administered at doses ≤200 mg/m2 three times a week is well tolerated and has hematologic activity in patients with MDS.

Novel P38 MAP Kinase Inhibitor and Anti-P38 RNA Interference as Potential Therapeutic Approaches in Myelodysplastic Syndromes.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 470-470
Author(s):  
Mani Mohindru ◽  
Perry Pahanish ◽  
Efstratios Katsoulidis ◽  
Robert Collins ◽  
Thomas Rogers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Map Kinase ◽  
P38 Mapk ◽  
Colony Formation ◽  
P38 Map Kinase ◽  
Hematopoietic Progenitors ◽  
P38 Inhibitor ◽  
Tnf Α ◽  
Ifn Γ

Abstract Cytokines such as TNF α, IFN γ and others have been implicated in the pathogenesis of ineffective hematopoiesis in MDS and are thought to lead to the high rate of apoptosis in hematopoietic progenitors. The p38 Mitogen Activated Protein Kinase (MAPK) is an evolutionary conserved enzyme that is involved in many cellular processes including stress signaling. We have previously shown that the p38 MAP kinase is strongly activated by IFNs, TNF α, TGF β and other inhibitory cytokines in normal primary hematopoietic progenitors and plays an important role in the negative regulation of normal hematopoiesis. In the present study, we determined the role of the p38 MAPK in the pathogenesis of MDS evaluated its inhibition as a potential therapeutic strategy in this disease. p38 MAPK inhibition was achieved by the use of a novel p38 inhibitor - SD-282, a specific inhibitor of p38α MAP kinase. SD-282 performs very similarly in animal and cell models to a p38 inhibitor now in the clinic. We also transfected primary hematopoietic cells with flurescent labeled siRNAs against p38 and successfully downregulated the levels of the protein. Using these approaches, we demonstrate that pharmacological inhibition of the p38 MAPK can reverse the growth inhibitory effects of TNF α and IFN γ on erythroid and myeloid colony formation. This reversal of TNF α mediated inhibition correlates with significant reduction of apoptosis seen in human hematopoeitic progenitors pretreated with p38 inhibitor SD-282. Having established the importance of p38 MAPK in cytokine mediated inhibition of normal hematopoiesis, we performed colony forming assays with bone marrow CD34+ cells from 8 patients with MDS in the presence of either pharmacologic or siRNA based inhibitors of p38. All patients had refractory cytopenias with multilineage dysplasia. Our data indicates that SD-282 treatment strongly enhances both erythroid and myeloid colony formation in MDS CD34+ bone marrow cells in vitro. This increase was not observed when these progenitors were grown in the presence of negative controls - SB 202474 and the MEK inhibitor PD 98059. Similarly, an increase in hematopoietic colony formation, though of a lesser magnitude was seen when MDS bone marrow progenitors were transfected with siRNAs against p38 MAPK. To further determine the role of cytokines in the pathogenesis of MDS, we also used bone marrow derived sera from the same MDS patients. Our studies show exposure to patient derived sera led to the phosphorylation/activation of p38 MAPK in normal hematopoietic progenitors when compared to sera from healthy volunteers. Our studies also demonstrate that bone marrow derived sera from MDS patients can inhibit erythroid and myeloid colony formation of normal hematopoietic progenitors. This inhibition can be reversed by blocking p38 MAPK using SD-282, other p38 inhibitors and siRNAs. This finding confirms the role of marrow cytokine /serum factors in the ineffective hematopoiesis seen in MDS and suggests the importance of p38 MAPK activation in this phenomenon. Thus our studies show the p38 MAPK may be a common effector of inhibitory cytokine signaling in normal and MDS hematopoietic cells. These results provide a strong rationale for using p38 inhibition as a novel treatment strategy for MDS. Supported by Harris Methodist Foundation Grant, VISN-17 New Investigator Grant and VA Research Corp Grant to AV.

scholarly journals Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3434-3443 ◽  
Author(s):  
Li Zhou ◽  
Aaron N. Nguyen ◽  
Davendra Sohal ◽  
Jing Ying Ma ◽  
Perry Pahanish ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Transforming Growth Factor ◽  
Expression Profiles ◽  
Bone Marrow Failure ◽  
Disease Suppression ◽  
Hematopoietic Progenitors ◽  
Cd34 Cells ◽  
Β Receptor ◽  
Pharmacologic Inhibition

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–β (TGF-β) 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-β pathway in this disease. Suppression of the TGF-β 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-β–mediated gene activation in BM stromal cells, and reverses TGF-β–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-β1. Moreover, in vitro pharmacologic inhibition of TBRI kinase leads to enhancement of hematopoiesis in varied morphologic MDS subtypes. These data directly implicate TGF-β signaling in the pathobiology of ineffective hematopoiesis and identify TBRI as a potential therapeutic target in low-risk MDS.

Abstract 17293: Hyperglycemia Enhances Pro-Inflammatory Properties of Macrophage-Derived Exosomes to Drive Hematopoiesis in Apolipoprotein E-Deficient Mouse

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Laura Bouchareychas ◽  
Phat Duong ◽  
Tuan Anh Phu ◽  
Eric Alsop ◽  
bessie meechoovet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Glucose ◽  
Vascular Inflammation ◽  
Cell Communication ◽  
Chow Diet ◽  
Hematopoietic Progenitors ◽  
Inflammatory Signaling ◽  
Accelerate Atherosclerosis

Introduction: Macrophage-derived exosomes have emerged as important mediators in cell-to-cell communication by influencing inflammatory signaling and the immune function. Hypothesis: We aimed to explore whether hyperglycemia can enhance intercellular communication between mature macrophages and hematopoietic progenitors via exosomes to promote inflammation and diabetic atherosclerosis. Methods: Bone marrow derived macrophages (BMDM) from C57BL/6 mice were cultured with normal (5.5 mM) or high glucose concentrations (25 mM). Exosomes were isolated by cushioned-density gradient ultracentrifugation method followed by nanoparticle tracking and western blot analysis. Inflammatory properties of high glucose exosomes (BMDM-HG-exo) or normoglycemic exosomes (BMDM-NG-exo) were tested in vitro by exposing them to naïve BMDM. The capacity for BMDM-derived exosomes to alter systemic and vascular inflammation were next tested by infusing 25-30 weeks-old ApoE -/- mice fed a chow diet with exosomes three times a week, for four weeks. Results: Our data show that BMDM-HG-exo can stimulate the expression of inflammatory cytokines and generate reactive oxygen species in recipient cultured BMDM. Furthermore, our findings show that intraperitoneally injected exosomes distribute to numerous organs and tissues including the bone marrow and the spleen. HG-exo enhance the expansion of multipotent and lineage committed hematopoietic progenitors in the spleen, leading to an enhanced atherosclerotic progression. Conclusions: We identify that exosomes derived from cultured BMDM exposed to high glucose have the capacity to exert inflammatory signaling in vitro , and in vivo. Our findings suggest that exosomes produced by macrophages exposed to hyperglycemia could represent an unsuspected source of inflammation to accelerate atherosclerosis in diabetes.

scholarly journals Chronic myelodysplastic syndrome (preleukemia) with the Philadelphia chromosome

Blood ◽  
1980 ◽  
Vol 56 (2) ◽  
pp. 262-264 ◽  
Author(s):  
DG Roth ◽  
CM Richman ◽  
JD Rowley
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Bone Marrow Cells ◽  
Philadelphia Chromosome ◽  
Laboratory Findings ◽  
Chronic Granulocytic Leukemia ◽  
Hematologic Disorder ◽  
Erythroid Hyperplasia ◽  
Granulocytic Colony

Abstract A patient with severe anemia, reticulocytopenia, and erythroid hyperplasia of the bone marrow developed fatal acute nonlymphocytic leukemia after 3 yr. A Philadelphia chromosome with the typical 9/22 translocation t(9q +;22q-) was identified by banding techniques in a small number of bone marrow cells throughout the preleukemic phase of the illness (14%--38% of metaphases) and during the acute transformation (50%). Granulocytic colony formation in vitro was abnormal in the preleukemic phase. The diagnosis of chronic granulocytic leukemia was excluded on the basis of clinical and laboratory findings. The identification of the Ph1 chromosome in this form of chronic myelodysplastic syndrome (preleukemia) provides a new example of a hematologic disorder predisposing to acute leukemia in which this chromosomal abnormality occurs.

scholarly journals Use of 5-fluorouracil to analyze the effect of macrophage inflammatory protein-1 alpha on long-term reconstituting stem cells in vivo

Blood ◽  
1993 ◽  
Vol 81 (6) ◽  
pp. 1497-1504 ◽  
Author(s):  
VF Quesniaux ◽  
GJ Graham ◽  
I Pragnell ◽  
D Donaldson ◽  
SD Wolpe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Inhibitory Effect ◽  
In Vivo Model ◽  
Hematopoietic Progenitors ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Abstract A macrophage-derived inhibitor of early hematopoietic progenitors (colony-forming unit-spleen, CFU-A) called stem cell inhibitor was found to be identical to macrophage inflammatory protein-1 alpha (MIP-1 alpha). We investigated the effect of MIP-1 alpha on the earliest stem cells that sustain long-term hematopoiesis in vivo in a competitive bone marrow repopulation assay. Because long-term reconstituting (LTR) stem cells are normally quiescent, an in vivo model was first developed in which they are triggered to cycle. A first 5-fluorouracil (5-FU) injection was used to eliminate later progenitors, causing the LTR stem cells, which are normally resistant to 5-FU, to enter the cell cycle and become sensitive to a second 5-FU injection administered 5 days later. Human MIP-1 alpha administered from day 0 to 7 was unable to prevent the depletion of the LTR stem cells by the second 5-FU treatment, as observed on day 7 in this model, suggesting that the LTR stem cells were not prevented from being triggered into cycle despite the MIP-1 alpha treatment. However, the MIP-1 alpha protocol used here did substantially decrease the number of more mature hematopoietic progenitors (granulocyte-macrophage colony-forming cells [CFC], burst- forming unit-erythroid, CFCmulti, and preCFCmulti) recovered in the bone marrow shortly after a single 5-FU injection. In vitro, MIP-1 alpha had no inhibitory effect on the ability of these progenitors to form colonies. This study confirms the in vivo inhibitory effect of MIP- 1 alpha on subpopulations of hematopoietic progenitors that are activated in myelodepressed animals. However, MIP-1 alpha had no effect on the long-term reconstituting stem cells in vivo under conditions in which it effectively reduced all later progenitors.

scholarly journals Heparanase regulates retention and proliferation of primitive Sca-1+/c-Kit+/Lin− cells via modulation of the bone marrow microenvironment

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 4934-4943 ◽  
Author(s):  
Asaf Spiegel ◽  
Eyal Zcharia ◽  
Yaron Vagima ◽  
Tomer Itkin ◽  
Alexander Kalinkovich ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Cathepsin K ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Progenitor ◽  
Cell Mobilization ◽  
Tumor Growth And Metastasis

Abstract Heparanase is involved in tumor growth and metastasis. Because of its unique cleavage of heparan sulfate, which binds cytokines, chemokines and proteases, we hypothesized that heparanase is also involved in regulation of early stages of hematopoiesis. We report reduced numbers of maturing leukocytes but elevated levels of undifferentiated Sca-1+/c-Kit+/Lin− cells in the bone marrow (BM) of mice overexpressing heparanase (hpa-Tg). This resulted from increased proliferation and retention of the primitive cells in the BM microenvironment, manifested in increased SDF-1 turnover. Furthermore, heparanase overexpression in mice was accompanied by reduced protease activity of MMP-9, elastase, and cathepsin K, which regulate stem and progenitor cell mobilization. Moreover, increased retention of the progenitor cells also resulted from up-regulated levels of stem cell factor (SCF) in the BM, in particular in the stem cell–rich endosteum and endothelial regions. Increased SCF-induced adhesion of primitive Sca-1+/c-Kit+/Lin− cells to osteoblasts was also the result of elevation of the receptor c-Kit. Regulation of these phenomena is mediated by hyperphosphorylation of c-Myc in hematopoietic progenitors of hpa-Tg mice or after exogenous heparanase addition to wildtype BM cells in vitro. Altogether, our data suggest that heparanase modification of the BM microenvironment regulates the retention and proliferation of hematopoietic progenitor cells.

scholarly journals Treatments targeting MDS genetics: a fool’s errand?

Hematology ◽  
2018 ◽  
Vol 2018 (1) ◽  
pp. 277-285 ◽  
Author(s):  
Amy E. DeZern
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Patient Outcomes ◽  
Myelodysplastic Syndromes ◽  
Bone Marrow Failure ◽  
Targeted Agents ◽  
Clonal Hematopoiesis ◽  
Myeloid Neoplasms ◽  
Improve Patient

Abstract The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure characteristically seen in patients. The heterogeneity of myelodysplastic syndrome pathobiology has historically posed a challenge to the development of newer therapies. Recent advances in molecular characterization of myelodysplastic syndromes are improving diagnostic accuracy, providing insights into pathogenesis, and refining therapeutic options for patients. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.

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