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.

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.

scholarly journals The ability of bone marrow progenitor cells to form colonies in ex vivo culture of MDS patients

2021 ◽  
Vol 4 ◽  
pp. 21-25
Author(s):  
Denys Bilko ◽  
Margaryta Pakharenko ◽  
Nadiia Bilko
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Progenitor Cells ◽  
Ex Vivo ◽  
Pathological Process ◽  
Hematopoietic Progenitor Cells ◽  
Refractory Anemia ◽  
Hematopoietic Progenitor ◽  
Ex Vivo Culture

The results of in vitro hematopoiesis studies have provided most of the knowledge about the organization, regulation, and development of the human hematopoietic system over the past three to four decades. However, due to the impossibility of an appropriate assessment of hematopoietic stem cells (HSC) in humans and because of the shortcomings of methodological approaches to determining the role of hematopoietic progenitor cells in the pathogenesis of MDS and to predicting the course of the pathological process, semiliquid agar cultures of bone marrow from patients with myelodysplastic syndrome were used. Myelodysplastic syndrome (MDS) refers to a clinically, morphologically, and genetically heterogeneous group of diseases characterized by clonalism and arising from mutations at the level of hematopoietic progenitor cells. Proliferation of such a mutated stem cell progenitors leads to ineffective maturation of myeloid lineage cells and dysplastic changes in the bone marrow (BM). The aim of the study was to establish the relationship between the functional activity of hematopoietic progenitor cells in the ex vivo culture and the activity of the pathological process in the myelodysplastic syndrome. We studied bone marrow samples from patients with the myelodysplastic syndrome, namely refractory anemia with excess blasts I (MDS RAEB I) and refractory anemia with excess blasts II (MDS RAEB II) and AML under conditions in vitro, as well as their clinical laboratory data. It was found that the percentage of blasts and myeloblasts in the samples of patients with AML and MDS RAEB II increased, compared to the samples of patients with MDS RAEB I (63.5±3.9 %, 18.05±1.01 % and 9.49±1.53 % respectively). An increase in the number of erythrocytes and hemoglobin content was noted in the group of patients with MDS RAEB I compared with MDS RAEB II (2.9±1.4×1012 / l and 105.04±3.6 g / l versus 9±0.8×1012 / l and 84.5±4.8 g / l, respectively). The analysis of the results of BM studies of patients with MDS in in vitro culture indicated a significant lag in the formation of cell aggregates during cultivation and a pronounced inhibition of the colony-forming ability of progenitor cells, compared to the control. A noticeable decrease in the colony-forming ability was observed in patients with MDS RAEB I, MDS RAEB II and AML in this sequence – 4.1±1.2 per 1×105 explanted cells, 3.2±0.9 per 1×105 explanted cells and 2.0±0.6 per 1×105 explanted cells, respectively. The analysis of hematological parameters and the results of BM cells cultivation at different stages of MDS indicates that the colony-forming ability of progenitor cells correlates with the depth of the pathological process.

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.

Suppression of Cyclin D 1 (CD1) by on 01910.Na Is Associated with Decreased Survival or Trisomy 8 Myelodysplastic Bone Marrow: A Potential Targetted Therapy for Trisomy 8 MDS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1651-1651
Author(s):  
Aarthi Shenoy ◽  
Loretta Pfannes ◽  
Francois Wilhelm ◽  
Manoj Maniar ◽  
Neal Young ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Cultured Cells ◽  
Bone Marrow Failure ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Diploid Cells

Abstract CD34 positive cells from patients with trisomy 8 myelodysplastic syndrome (MDS) have pronounced expression of early apoptotic markers compared to normal hematopoietic cells. However, trisomy 8 clones persist in patients with bone marrow failure and expand following immunosuppression (Sloand EM et al; Blood2005; 106(3):841). We have demonstrated up-regulation of c-myc, survivin, and CD1 in CD34 cells of patients with trisomy 8 (Sloand et al; Blood2007; 109(6):2399). Employing siRNA mediated knockdown of the anti-apoptotic protein survivin, we demonstrated a decrease in trisomy 8 cell growth and postulated that increased Cyclin D1 caused the upregulation of survivin resulting in resistance of these cells to apoptosis. Using fluorescent in situ hybridization (FISH) we showed that the novel styryl sulfone, ON 01910.Na (Vedula MS et al; European Journal of Medicinal Chemistry2003;38:811), inhibits cyclin D1 accumulation and is selectively toxic to trisomy 8 cells while promoting maturation of diploid cells. Flow cytometry of cultured cells demonstrated increased proportions of mature CD15 positive myeloid cells and decreased number of immature CD33+ cells or CD34+ blasts (Sloand EM et al; Blood2007;110:822). These encouraging in vitro data led to a phase I/II trial of ON 01910.Na in MDS patients with refractory anemia with excess blasts who had IPSS =/> int-2. This study was designed to assess the safety, and activity of escalating doses of ON 01910.Na (800 mg/m2/day × 3 days, 800 mg/m2/day × 5 days, 1500 mg/m2/day × 5 days, 1800 mg/m2/day × 5 days every 2 weeks) in MDS patients. To date five MDS patients have been treated with ON 01910.Na for 4 to 16 weeks in the first two dose cohorts. Two patients had isolated trisomy 8, two had complex cytogenetic abnormalities including trisomy 8 in all aneuploid cells, and one had monosomy 7. Three and five day infusions were well tolerated. Pharmakokinetic analysis showed that the half life of the drug is 1.3 ± 0.5 hours without signs of drug accumulation. Four of five patients demonstrated a rapid and significant decrease in the number of peripheral blasts and aneuploid cells after 4 weeks of therapy (see below), concomitantly with increases in neutrophil and/or platelet counts in four patients. All four patients exhibiting a biological effect of drug treatment had trisomy 8 in their aneuploid clone prior to therapy. One monosomy 7 patient, previously refractory to EPO became responsive to Darbopoietin and another trisomy 8 patient became platelet-transfusion independent. In this early safety trial, ON 01910.Na demonstrates efficacy at early timepoints with respect to improved cytopenias and decreased blast counts. Continued enrollment and long term follow-up will further detail clinical efficacy and impact on the long term prognosis of high risk MDS patients treat with this drug. Figure Figure

Sign in / Sign up

Export Citation Format

Share Document