scholarly journals HDAC6 promotes PMA-induced megakaryocyte differentiation of K562 cells by regulating ROS levels via NOX4 and repressing Glycophorin A

2019 ◽  
Author(s):  
Githavani Kummari ◽  
Ravi K Gutti ◽  
Arunasree M. Kalle
Keyword(s):  
Progenitor Cells ◽  
Marker Gene ◽  
K562 Cells ◽  
Glycophorin A ◽  
List Type ◽  
Down Regulation ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Lineage Marker ◽  
Megakaryocyte Differentiation

AbstractThe human erythroleukemia (K562) cells are considered as bipotent megakaryocyte-erythroid progenitor cells and the differentiation of these cells to megakaryocytes (MK) in the presence of phorbol 12-myristate 13-acetate (PMA) mimics in vivo differentiation of MEP (megakaryocyte-erythroid progenitor) cells in the bone marrow. Histone deacetylases (HDACs) are involved in gene suppression and their roles during the MK differentiation remains largely undefined. In the present study, we have studied the expression levels of class I and class II HDACs during phorbol 12-myristate 13-acetate (PMA)-induced differentiation of K562 cells to MK. Class IIb HDACs (HDAC6 & HDAC10) were significantly up regulated time dependently upto 4 days of PMA-induced MK differentiation along with decreased acetylation levels of H3K9 and H3K56. Pharmacological inhibition and knockdown studies of HDAC6 using tubastatin A (TubA) and shRNA-HDAC6 respectively, during MK differentiation resulted in down regulation of MK lineage marker CD61 and up regulation of erythroid lineage gene glycophorin A (GYPA). HDAC6 over expression in K562 cells showed significant up regulation of CD61, MK transcription factors (FOG1 and GATA2) and down regulation of GYPA. ChIP-PCR studies showed enrichment of HDAC6 protein on GYPA promoter during differentiation indicating GYPA gene repression by HDAC6. Further studies on elucidating the role of HDAC6 in MK differentiation clearly indicated that HDAC6 is required for the production of sustainable levels of reactive oxygen species (ROS), an important regulator of MK differentiation, via NOX4.- ROS-HDAC6 circuit. In this study, we provide the first evidence that during PMA-induced megakaryocyte differentiation of K562 cells, HDAC6 represses erythroid lineage marker gene, GYPA, and promotes the sustainable levels of ROS via NOX4 required for MK differentiation.Key pointsHDAC6 upregulated during MK differentiation is involved in sustainable production of ROS via the circuit - HDAC6-NOX4-ROS-HDAC6.HDAC6 inhibits erythroid lineage gene, GYPA, by forming a repressor complex over the promoter region.

Receptor binding cancer antigen expressed on SiSo cells, a novel regulator of apoptosis of erythroid progenitor cells

Blood ◽  
2001 ◽  
Vol 98 (2) ◽  
pp. 313-321 ◽  
Author(s):  
Takamitsu Matsushima ◽  
Manabu Nakashima ◽  
Koichi Oshima ◽  
Yasunobu Abe ◽  
Junji Nishimura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Receptor Binding ◽  
Transferrin Receptor ◽  
Human Peripheral Blood ◽  
Soluble Form ◽  
Glycophorin A ◽  
Cancer Antigen ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

To better understand the control of apoptosis during erythropoiesis, this study investigated the role of a novel tumor-associated antigen, RCAS1 (receptor binding cancer antigen expressed on SiSo cells), with regard to the regulation of apoptosis of erythroid progenitor cells. Erythroid colony-forming cells (ECFCs) purified from human peripheral blood were used. Binding experiments of RCAS1 showed that ECFCs abundantly expressed receptors (RCAS1R) for RCAS1 and that the degree of binding of RCAS1 to the receptors diminished rapidly during erythroid maturation in vitro. When the soluble form of RCAS1 was added to the cultures, ECFCs underwent apoptosis, including collapse of the mitochondrial transmembrane potential, and activation of caspases 8 and 3. The addition of an anti-Fas blocking antibody or Fas-Fc failed to reduce the apoptosis induced by RCAS1, thereby indicating that effects of RCAS1 are independent of Fas activation. When binding of RCAS1 to normal bone marrow cells was analyzed, RCAS1R was evident on cells with an immature erythroid phenotype (transferrin receptor+/glycophorin A−) but not with a mature phenotype (transferrin receptor−/glycophorin A+). Histochemical staining revealed the expression of RCAS1 in the cytoplasm of bone marrow macrophages. These findings indicate that RCAS1, which is mainly produced by macrophages in hematopoietic tissue, may have a crucial role in controlling erythropoiesis by modulating apoptosis of erythroid progenitor cells via a Fas-independent mechanism.

Epo-Independent Proliferation and Differentiation of Genetically Modified Erythroid Progenitor Cells Using a Chemical Inducer of Dimerization.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1159-1159
Author(s):  
Chris P. Miller ◽  
Songmao Zheng ◽  
C. Anthony Blau
Keyword(s):  
Progenitor Cells ◽  
Erythroid Cell ◽  
Glycophorin A ◽  
Erythroid Cells ◽  
Erythroid Progenitor ◽  
Cell Production ◽  
Erythroid Progenitor Cells ◽  
Proliferation And Differentiation ◽  
Cells Cultured ◽  
Chemical Inducer Of Dimerization

Abstract Recombinant human erythropoietin (Epo) revolutionized the care of anemia in cancer. In light of emerging (albeit controversial) roles for Epo in supporting tumor growth, it may be useful to develop Epo-independent methods for regulating red blood cell production. Previous studies in this laboratory established that marrow transduced with conditional derivatives of fibroblast growth factor receptor-1 (F36VFGFR1) and the thrombopoietin receptor (F36VMpl) can support the chemical inducer of dimerization (CID)-dependent production of erythroid cells in transplanted mice. In the current study, we used human CD34+ cord blood (CB) cells to test whether CID-regulated red cell production might require collaboration between CID-initiated signals and those provided by Epo. CD34+ CB cells cultured in the absence of Epo did not proliferate and retained expression of the myeloid marker CD33. Epo (5U/mL) promoted proliferative expansion (66.2-fold in 12 days) and CD33 expression was lost as the cells differentiated to mature, glycophorin A+ erythroid cells (92.9 +/− 1.8%, n=3). Addition of a soluble human Epo receptor extracellular domain (shEpoR) at a concentration of 3ug/mL completely blocked Epo-dependent proliferation and similar to cells cultured without Epo, they retained expression of CD33. Addition of CID (100nM AP20187) to F36VMpl-transduced CD34+ CB cells in the absence of Epo promoted proliferative expansion (89.8-fold in 12 days) and differentiation as glycophorin A+ erythroid cells (77.2 +/− 4.8%, n=3). These CID responses were not significantly affected by the addition of shEpoR, as CID induced both mitogenic expansion (84.5 fold in 12 days) and differentiation as glycophorin A+ erythroid cells (74.2 +/− 6.7%, n=3) in the presence of concentrations of shEpoR that blocked Epo responses. These data suggest that F36VMpl does not require Epo signaling to support the proliferation and differentiation of human erythroid progenitor cells, and further define an Epo-independent method of erythroid cell production.

scholarly journals Cell-to-cell variability in JAK2/STAT5 pathway components and cytoplasmic volumes define survival threshold in erythroid progenitor cells

2019 ◽  
Author(s):  
Lorenz Adlung ◽  
Paul Stapor ◽  
Christian Tönsing ◽  
Leonard Schmiester ◽  
Luisa E. Schwarzmüller ◽  
...  
Keyword(s):  
Single Cell ◽  
Progenitor Cells ◽  
Cell Population ◽  
Population Level ◽  
Minimal Amount ◽  
List Type ◽  
Erythroid Progenitor ◽  
Binary Decision ◽  
Erythroid Progenitor Cells ◽  
Cell To Cell Variability

SummarySurvival or apoptosis is a binary decision in individual cells. Yet, at the cell population level, a graded increase in survival of CFU-E cells is observed upon stimulation with Erythropoietin (Epo). To identify components of JAK2/STAT5 signal transduction that contribute to the graded population response, a cell population-level model calibrated with experimental data was extended to study the behavior in single cells. The single-cell model showed that the high cell-to-cell variability in nuclear phosphorylated STAT5 is caused by variability in the amount of EpoR:JAK2 complexes and of SHP1 as well as the extent of nuclear import due to the large variance in the cytoplasmic volume of CFU-E cells. 24 to 118 pSTAT5 molecules in the nucleus for 120 min are sufficient to ensure cell survival. Thus, variability in membrane-associated processes are responsible to convert a switch-like behavior at the single-cell level to a graded population level response.HighlightsMathematical modeling enables integration of heterogeneous dataSingle-cell modeling captures binary decision processMultiple sources of cell-to-cell variability in erythroid progenitor cellsMinimal amount of active STAT5 sufficient for survival of erythroid progenitor cells

Human thymic epithelial cells maintain long-term survival of clonogenic myeloid and erythroid progenitor cells in vitro

2000 ◽  
Vol 111 (1) ◽  
pp. 363-370 ◽  
Author(s):  
Katsuto Takenaka ◽  
Mine Harada ◽  
Tomoaki Fujisaki ◽  
Koji Nagafuji ◽  
Shinichi Mizuno ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Progenitor Cells ◽  
Thymic Epithelial Cells ◽  
Erythroid Progenitor ◽  
Term Survival ◽  
Long Term Survival ◽  
Erythroid Progenitor Cells

scholarly journals Fetal erythropoiesis in steel mutant mice. III. Defect in differentiation from BFU-E to CFU-E during early development

Blood ◽  
1978 ◽  
Vol 51 (3) ◽  
pp. 539-547 ◽  
Author(s):  
DH Chui ◽  
SK Liao ◽  
K Walker
Keyword(s):  
Progenitor Cells ◽  
Early Development ◽  
The Other ◽  
Mutant Mice ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells ◽  
Other Hand ◽  
Colony Forming Units ◽  
Fetal Erythropoiesis

Abstract Erythroid progenitor cells in +/+ and Sl/Sld fetal livers manifested as burst-forming units-erythroid (BFU-E) and colony-forming units- erythroid (CFU-E) were assayed in vitro during early development. The proportion of BFU-E was higher as mutant than in normal fetal livers. On the other hand, the proportion of CFU-E was less in the mutant than in the normal. These results suggest that the defect in Sl/Sld fetal hepatic erythropoiesis is expressed at the steps of differentiation that effect the transition from BFU-E to CFU-E.

scholarly journals The Raf‐1 Protein Mediates Insulin‐Like Growth Factor‐Induced Proliferation of Erythroid Progenitor Cells

Stem Cells ◽  
1998 ◽  
Vol 16 (3) ◽  
pp. 200-207 ◽  
Author(s):  
Marilyn R. Sanders ◽  
Hsienwie Lu ◽  
Frederick Walker ◽  
Sandra Sorba ◽  
Nicholas Dainiak
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

scholarly journals Tumor Immune Evasion Induced by Dysregulation of Erythroid Progenitor Cells Development

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 870
Author(s):  
Tomasz M. Grzywa ◽  
Magdalena Justyniarska ◽  
Dominika Nowis ◽  
Jakub Golab
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Progenitor Cells ◽  
Cancer Progression ◽  
Immune Evasion ◽  
Transforming Growth Factor ◽  
Early Stage ◽  
Interleukin 10 ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

Cancer cells harness normal cells to facilitate tumor growth and metastasis. Within this complex network of interactions, the establishment and maintenance of immune evasion mechanisms are crucial for cancer progression. The escape from the immune surveillance results from multiple independent mechanisms. Recent studies revealed that besides well-described myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) or regulatory T-cells (Tregs), erythroid progenitor cells (EPCs) play an important role in the regulation of immune response and tumor progression. EPCs are immature erythroid cells that differentiate into oxygen-transporting red blood cells. They expand in the extramedullary sites, including the spleen, as well as infiltrate tumors. EPCs in cancer produce reactive oxygen species (ROS), transforming growth factor β (TGF-β), interleukin-10 (IL-10) and express programmed death-ligand 1 (PD-L1) and potently suppress T-cells. Thus, EPCs regulate antitumor, antiviral, and antimicrobial immunity, leading to immune suppression. Moreover, EPCs promote tumor growth by the secretion of growth factors, including artemin. The expansion of EPCs in cancer is an effect of the dysregulation of erythropoiesis, leading to the differentiation arrest and enrichment of early-stage EPCs. Therefore, anemia treatment, targeting ineffective erythropoiesis, and the promotion of EPC differentiation are promising strategies to reduce cancer-induced immunosuppression and the tumor-promoting effects of EPCs.

scholarly journals Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor.

1995 ◽  
Vol 15 (6) ◽  
pp. 3147-3153 ◽  
Author(s):  
G A Blobel ◽  
C A Sieff ◽  
S H Orkin
Keyword(s):  
Bone Marrow ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Progenitor Cells ◽  
Erythroid Cell ◽  
High Dose ◽  
Dependent Manner ◽  
Erythroid Progenitor ◽  
Erythroid Progenitor Cells

High-dose estrogen administration induces anemia in mammals. In chickens, estrogens stimulate outgrowth of bone marrow-derived erythroid progenitor cells and delay their maturation. This delay is associated with down-regulation of many erythroid cell-specific genes, including alpha- and beta-globin, band 3, band 4.1, and the erythroid cell-specific histone H5. We show here that estrogens also reduce the number of erythroid progenitor cells in primary human bone marrow cultures. To address potential mechanisms by which estrogens suppress erythropoiesis, we have examined their effects on GATA-1, an erythroid transcription factor that participates in the regulation of the majority of erythroid cell-specific genes and is necessary for full maturation of erythrocytes. We demonstrate that the transcriptional activity of GATA-1 is strongly repressed by the estrogen receptor (ER) in a ligand-dependent manner and that this repression is reversible in the presence of 4-hydroxytamoxifen. ER-mediated repression of GATA-1 activity occurs on an artificial promoter containing a single GATA-binding site, as well as in the context of an intact promoter which is normally regulated by GATA-1. GATA-1 and ER bind to each other in vitro in the absence of DNA. In coimmunoprecipitation experiments using transfected COS cells, GATA-1 and ER associate in a ligand-dependent manner. Mapping experiments indicate that GATA-1 and the ER form at least two contacts, which involve the finger region and the N-terminal activation domain of GATA-1. We speculate that estrogens exert effects on erythropoiesis by modulating GATA-1 activity through protein-protein interaction with the ER. Interference with GATA-binding proteins may be one mechanism by which steroid hormones modulate cellular differentiation.

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