Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells

Blood ◽  
2004 ◽  
Vol 103 (2) ◽  
pp. 538-544 ◽  
Author(s):  
Silke Appel ◽  
Andreas M. Boehmler ◽  
Frank Grünebach ◽  
Martin R. Müller ◽  
Anette Rupf ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Progenitor Cells ◽  
Imatinib Mesylate ◽  
Tyrosine Kinases ◽  
Kinase Inhibitor ◽  
Hematopoietic Cells ◽  
Signal Transduction Pathway ◽  
Myelogenous Leukemia ◽  
And Function

Abstract Imatinib mesylate (STI571) is a competitive Bcr-Abl tyrosine kinase inhibitor and has yielded encouraging results in treatment of chronic myelogenous leukemia (CML) and gastrointestinal stroma tumors (GISTs). Apart from inhibition of the Abl protein tyrosine kinases, it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases. In vitro studies have revealed that imatinib mesylate can inhibit growth of cell lines and primitive malignant progenitor cells in CML expressing Bcr-Abl. However, little is known about the effects of imatinib mesylate on nonmalignant hematopoietic cells. In the current study we demonstrate that in vitro exposure of mobilized human CD34+ progenitors to therapeutic concentrations of imatinib mesylate (1-5 μM) inhibits their differentiation into dendritic cells (DCs). DCs obtained after 10 to 16 days of culture in the presence of imatinib mesylate showed concentration-dependent reduced expression levels of CD1a and costimulatory molecules such as CD80 and CD40. Furthermore, exposure to imatinib mesylate inhibited the induction of primary cytotoxic T-lymphocyte (CTL) responses. The inhibitory effects of imatinib mesylate were accompanied by down-regulation of nuclear localized RelB protein. Our results demonstrate that imatinib mesylate can act on normal hematopoietic cells and inhibits the differentiation and function of DCs, which is in part mediated via the nuclear factor κB signal transduction pathway.

scholarly journals Targeting USP47 overcomes tyrosine kinase inhibitor resistance and eradicates leukemia stem/progenitor cells in chronic myelogenous leukemia

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hu Lei ◽  
Han-Zhang Xu ◽  
Hui-Zhuang Shan ◽  
Meng Liu ◽  
Ying Lu ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Drug Targets ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Tki Resistance

AbstractIdentifying novel drug targets to overcome resistance to tyrosine kinase inhibitors (TKIs) and eradicating leukemia stem/progenitor cells are required for the treatment of chronic myelogenous leukemia (CML). Here, we show that ubiquitin-specific peptidase 47 (USP47) is a potential target to overcome TKI resistance. Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo. The knockout of Usp47 significantly inhibits BCR-ABL and BCR-ABLT315I-induced CML in mice with the reduction of Lin−Sca1+c-Kit+ CML stem/progenitor cells. Mechanistic studies show that stabilizing Y-box binding protein 1 contributes to USP47-mediated DNA damage repair in CML cells. Inhibiting USP47 by P22077 exerts cytotoxicity to CML cells with or without TKI resistance in vitro and in vivo. Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

scholarly journals Sepsis Inflammation Impairs the Generation of Functional Dendritic Cells by Targeting Their Progenitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Jie Lu ◽  
Kun Sun ◽  
Huiping Yang ◽  
Dan Fan ◽  
He Huang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Tnf Α ◽  
Ifn Γ ◽  
And Function ◽  
Antigen Presenting ◽  
The Impact

BackgroundSepsis is a complex systemic immune dysfunction syndrome induced by infection. Sepsis has a high mortality rate, with most patients dying due to systemic organ failure or secondary infection. Dendritic cells (DCs) are professional antigen-presenting cells. Upon infection with microbes, DCs are activated to induce adaptive immune responses for controlling infection. DC generation and function are impaired during sepsis; however, the underlying mechanisms remain largely unknown.MethodsPeripheral blood samples from sepsis patients were collected to examine DC subsets, DC progenitors, and apoptosis of DCs by flow cytometer. In vitro induction of DCs from hematopoietic stem/progenitor cells were established and a variety of sepsis-associated inflammatory mediators [e.g., interferon-gamma (IFN-γ), interleukin-1beta (IL-1β), tumor necrosis factor-alpha (TNF-α) and granulocyte-colony stimulating factor (G-CSF)] and Lipopolysaccharide (LPS) were determined for the impact on DC generation and function in vitro.ResultsOur results demonstrate that sepsis-induced systemic inflammation impairs the capacity of hematopoietic stem and progenitor cells (HSPCs) to produce DCs, including conventional DCs (cDCs) and plasmacytoid DCs (pDCs). We investigated peripheral blood (PB) samples from 34 pediatric patients on days 1 to 7 following diagnosis. Compared to healthy donors (n = 18), the sepsis patients exhibited a significantly fewer percentage and number of pDCs and cDCs, and a lower expression of antigen presenting molecule HLD-DR and co-stimulatory molecules (e.g., CD86) on the surface of DCs. This sepsis-induced DC impairment was associated with significantly increased apoptotic death of DCs and marked decreases of progenitor cells that give rise to DCs. Furthermore, we observed that among the tested sepsis-associated cytokines (e.g., IFN-γ, IL-1β, TNF-α, and G-CSF), G-CSF and IFN-γ impaired DC development from cultured HSPCs. G-CSF also markedly decreased the expression of HLA-DR on HSPC-derived DCs and their cytokine production, including IL-12 and IFN-β.ConclusionsCollectively, these findings indicate that sepsis impairs the survival of functional DCs and their development from HSPCs. Strategies for improving DC reconstitution following sepsis may restore DC progenitors and their associated function.

scholarly journals Moving on up: Second-Line Agents as Initial Treatment for Newly-Diagnosed Patients with Chronic Phase CML

2011 ◽  
Vol 5 ◽  
pp. CMO.S6416 ◽  
Author(s):  
Marie P. Shieh ◽  
Masato Mitsuhashi ◽  
Michael Lilly
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Protein Tyrosine

The treatment of chronic myelogenous leukemia (CML) was revolutionized by the development of imatinib mesylate, a small molecule inhibitor of several protein tyrosine kinases, including the ABL1 protein tyrosine kinase. The current second generation of FDA-approved ABL tyrosine kinase inhibitors, dasatinib and nilotinib, are more potent inhibitors of BCR-ABL1 kinase in vitro. Originally approved for the treatment of patients who were refractory to or intolerant of imatinib, dasatinib and nilotinib are now also FDA approved in the first-line setting. The choice of tyrosine kinase inhibitor (ie, standard or high dose imatinib, dasatinib, nilotinib) to use for initial therapy in chronic-phase CML (CML-CP) will not always be obvious. Therapy selection will depend on both clinical and molecular factors, which we will discuss in this review.

Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate

Blood ◽  
2005 ◽  
Vol 106 (12) ◽  
pp. 3958-3961 ◽  
Author(s):  
Jörg Cammenga ◽  
Stefan Horn ◽  
Ulla Bergholz ◽  
Gunhild Sommer ◽  
Peter Besmer ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Therapeutic Option ◽  
Extracellular Domain ◽  
Genetic Alterations ◽  
Myelogenous Leukemia ◽  
Core Binding Factor ◽  
Kit Receptor ◽  
Binding Factor

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.

scholarly journals Primitive hematopoietic cells in murine bone marrow express the CD34 antigen

Blood ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3774-3784 ◽  
Author(s):  
F Morel ◽  
SJ Szilvassy ◽  
M Travis ◽  
B Chen ◽  
A Galy
Keyword(s):  
Stem Cells ◽  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Progenitor Cells ◽  
Significant Proportion ◽  
Hematopoietic Cells ◽  
Full Detail ◽  
Hematopoietic Stem ◽  
Cd34 Antigen

The CD34 antigen is expressed on most, if not all, human hematopoietic stem cells (HSCs) and hematopoietic progenitor cells, and its use for the enrichment of HSCs with repopulating potential is well established. However, despite homology between human and murine CD34, its expression on subsets of primitive murine hematopoietic cells has not been examined in full detail. To address this issue, we used a novel monoclonal antibody against murine CD34 (RAM34) to fractionate bone marrow (BM) cells that were then assayed in vitro and in vivo with respect to differing functional properties. A total of 4% to 17% of murine BM cells expressed CD34 at intermediate to high levels, representing a marked improvement over the resolution obtained with previously described polyclonal anti-CD34 antibodies. Sixty percent of CD34+ BM cells lacked lineage (Lin) markers expressed on mature lymphoid or myeloid cells. Eighty-five percent of Sca-1+Thy-1(10)Lin- /10 cells that are highly enriched in HSCs expressed intermediate, but not high, levels of CD34 antigen. The remainder of these phenotypically defined stem cells were CD34-. In vitro colony-forming cells, day-8 and -12 spleen colony-forming units (CFU-S), primitive progenitors able to differentiate into B lymphocytes in vitro or into T lymphocytes in SCID mice, and stem cells with radioprotective and competitive long-term repopulating activity were all markedly enriched in the CD34+ fraction after single-parameter cell sorting. In contrast, CD34-BM cells were depleted of such activities at the cell doses tested and were capable of only short-term B-cell production in vitro. The results indicate that a significant proportion of murine HSCs and multilineage progenitor cells express detectable levels of CD34, and that the RAM34 monoclonal antibody is a useful tool to subset primitive murine hematopoietic cells. These findings should facilitate more direct comparisons of the biology of CD34+ murine and human stem and progenitor cells.

scholarly journals Inhibition of O-GlcNAc Transferase Alters the Differentiation and Maturation Process of Human Monocyte Derived Dendritic Cells

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3312
Author(s):  
Matjaž Weiss ◽  
Marko Anderluh ◽  
Martina Gobec
Keyword(s):  
Dendritic Cells ◽  
Posttranslational Modification ◽  
Human Monocyte ◽  
T Cell Differentiation ◽  
Maturation Process ◽  
Hla Dr ◽  
Glcnac Transferase ◽  
And Function

The O-GlcNAcylation is a posttranslational modification of proteins regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase. These enzymes regulate the development, proliferation and function of cells, including the immune cells. Herein, we focused on the role of O-GlcNAcylation in human monocyte derived dendritic cells (moDCs). Our study suggests that inhibition of OGT modulates AKT and MEK/ERK pathways in moDCs. Changes were also observed in the expression levels of relevant surface markers, where reduced expression of CD80 and DC-SIGN, and increased expression of CD14, CD86 and HLA-DR occurred. We also noticed decreased IL-10 and increased IL-6 production, along with diminished endocytotic capacity of the cells, indicating that inhibition of O-GlcNAcylation hampers the transition of monocytes into immature DCs. Furthermore, the inhibition of OGT altered the maturation process of immature moDCs, since a CD14medDC-SIGNlowHLA-DRmedCD80lowCD86high profile was noticed when OGT inhibitor, OSMI-1, was present. To evaluate DCs ability to influence T cell differentiation and polarization, we co-cultured these cells. Surprisingly, the observed phenotypic changes of mature moDCs generated in the presence of OSMI-1 led to an increased proliferation of allogeneic T cells, while their polarization was not affected. Taken together, we confirm that shifting the O-GlcNAcylation status due to OGT inhibition alters the differentiation and function of moDCs in in vitro conditions.

Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib

Blood ◽  
2003 ◽  
Vol 101 (11) ◽  
pp. 4611-4614 ◽  
Author(s):  
Amie S. Corbin ◽  
Paul La Rosée ◽  
Eric P. Stoffregen ◽  
Brian J. Druker ◽  
Michael W. Deininger
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Imatinib Resistance ◽  
Abl Kinase ◽  
Cellular Assays ◽  
Kinase Domain Mutations

Abstract Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance.While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.

Control of N-cadherin-mediated intercellular adhesion in migrating neural crest cells in vitro

1995 ◽  
Vol 108 (12) ◽  
pp. 3839-3853 ◽  
Author(s):  
F. Monier-Gavelle ◽  
J.L. Duband
Keyword(s):  
Neural Crest ◽  
Tyrosine Kinases ◽  
Brefeldin A ◽  
Neural Crest Cells ◽  
Cell Aggregation ◽  
Phosphatase Inhibitors ◽  
Intercellular Contacts ◽  
And Function ◽  
Cell Cell

Dispersion of neural crest cells and their ultimate regroupment into peripheral ganglia are associated with precisely coordinated regulations both in time and space of the expression and function of cell adhesion receptors. In particular, the disappearance of N-cadherin from the cell surface at the onset of migration and its reexpression during cell aggregation suggest that, during migration, N-cadherin expression is repressed in neural crest cells. In the present study, we have analyzed in vitro the mechanism of control of N-cadherin expression and function in migrating neural crest cells. Although these cells moved as a dense population, each individual did not establish extensive and permanent intercellular contacts with its neighbors. However, cells synthesized and expressed mature N-cadherin molecules at levels comparable to those found in cells that exhibit stable intercellular contacts, but in contrast to them, the bulk of N-cadherin molecules was not connected with the cytoskeleton. We next determined which intracellular events are responsible for the instability of the N-cadherin junctions in neural crest cells using various chemical agents known to affect signal transduction processes. Agents that block a broad spectrum of serine-threonine kinases (6-dimethylaminopurine, H7 and staurosporine) or that affect selectively protein kinases C (bisindolylmaleimide and sphingosine), inhibitors of protein tyrosine kinases (erbstatin, herbimycin A, and tyrphostins), and inhibitors of phosphatases (vanadate) all restored tight cell-cell associations among neural crest cells, accompanied by a slight increase in the overall cellular content of N-cadherin and its accumulation to the regions of intercellular contacts. The effect of the kinase and phosphatase blockers was inhibitable by agents known to affect protein synthesis (cycloheximide) and exportation (brefeldin A), indicating that the restored cell-cell contacts were mediated chiefly by an intracellular pool of N-cadherin molecules recruited to the membrane. Finally, N-cadherin molecules were constitutively phosphorylated in migrating neural crest cells, but their level and state of phosphorylation were apparently not modified in the presence of kinase and phosphatase inhibitors. These observations therefore suggest that N-cadherin-mediated cell-cell interactions are not stable in neural crest cells migrating in vitro, and that they are under the control of a complex cascade of intracellular signals involving kinases and phosphatases and probably elicited by surface receptors.

scholarly journals Murine yolk sac endoderm- and mesoderm-derived cell lines support in vitro growth and differentiation of hematopoietic cells

Blood ◽  
1994 ◽  
Vol 83 (9) ◽  
pp. 2436-2443 ◽  
Author(s):  
MC Yoder ◽  
VE Papaioannou ◽  
PP Breitfeld ◽  
DA Williams
Keyword(s):  
Progenitor Cells ◽  
Cell Lines ◽  
Stromal Cell ◽  
Hematopoietic Cells ◽  
Yolk Sac ◽  
Hematopoietic Progenitor Cells ◽  
Visceral Endoderm ◽  
Hematopoietic Progenitor

Abstract The mechanisms involved in the induction of yolk sac mesoderm into blood islands and the role of visceral endoderm and mesoderm cells in regulating the restricted differentiation and proliferation of hematopoietic cells in the yolk sac remain largely unexplored. To better define the role of murine yolk sac microenvironment cells in supporting hematopoiesis, we established cell lines from day-9.5 gestation murine yolk sac visceral endoderm and mesoderm layers using a recombinant retrovirus vector containing Simian virus 40 large T- antigen cDNA. Obtained immortalized cell lines expressed morphologic and biosynthetic features characteristic of endoderm and mesoderm cells from freshly isolated yolk sacs. Similar to the differentiation of blood island hematopoietic cells in situ, differentiation of hematopoietic progenitor cells in vitro into neutrophils was restricted and macrophage production increased when bone marrow (BM) progenitor cells were cultured in direct contact with immortalized yolk sac cell lines as compared with culture on adult BM stromal cell lines. Yolk sac- derived cell lines also significantly stimulated the proliferation of hematopoietic progenitor cells compared with the adult BM stromal cell lines. Thus, yolk sac endoderm- and mesoderm-derived cells, expressing many features of normal yolk sac cells, alter the growth and differentiation of hematopoietic progenitor cells. These cells will prove useful in examining the cellular interactions between yolk sac endoderm and mesoderm involved in early hematopoietic stem cell proliferation and differentiation.

Efficacy of STI571, an Abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against Bcr-Abl–positive cells

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3195-3199 ◽  
Author(s):  
J. Tyler Thiesing ◽  
Sayuri Ohno-Jones ◽  
Kathryn S. Kolibaba ◽  
Brian J. Druker
Keyword(s):  
Clinical Trials ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Abl Tyrosine Kinase ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Chronic myelogenous leukemia (CML), a malignancy of a hematopoietic stem cell, is caused by the Bcr-Abl tyrosine kinase. STI571(formerly CGP 57148B), an Abl tyrosine kinase inhibitor, has specific in vitro antileukemic activity against Bcr-Abl–positive cells and is currently in Phase II clinical trials. As it is likely that resistance to a single agent would be observed, combinations of STI571 with other antileukemic agents have been evaluated for activity against Bcr-Abl–positive cell lines and in colony-forming assays in vitro. The specific antileukemic agents tested included several agents currently used for the treatment of CML: interferon-alpha (IFN), hydroxyurea (HU), daunorubicin (DNR), and cytosine arabinoside (Ara-C). In proliferation assays that use Bcr-Abl–expressing cells lines, the combination of STI571 with IFN, DNR, and Ara-C showed additive or synergistic effects, whereas the combination of STI571 and HU demonstrated antagonistic effects. However, in colony-forming assays that use CML patient samples, all combinations showed increased antiproliferative effects as compared with STI571 alone. These data indicate that combinations of STI571 with IFN, DNR, or Ara-C may be more useful than STI571 alone in the treatment of CML and suggest consideration of clinical trials of these combinations.

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