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1.
Sci Rep ; 12(1): 19660, 2022 11 16.
Article in English | MEDLINE | ID: mdl-36385153

ABSTRACT

Multiple myeloma (MM) remains an incurable malignancy of plasma cells despite constantly evolving therapeutic approaches including various types of immunotherapy. Increased arginase activity has been associated with potent suppression of T-cell immune responses in different types of cancer. Here, we investigated the role of arginase 1 (ARG1) in Vκ*MYC model of MM in mice. ARG1 expression in myeloid cells correlated with tumor progression and was accompanied by a systemic drop in ʟ-arginine levels. In MM-bearing mice antigen-induced proliferation of adoptively transferred T-cells was strongly suppressed and T-cell proliferation was restored by pharmacological arginase inhibition. Progression of Vκ*MYC tumors was significantly delayed in mice with myeloid-specific ARG1 deletion. Arginase inhibition effectively inhibited tumor progression although it failed to augment anti-myeloma effects of bortezomib. However, arginase inhibitor completely prevented development of bortezomib-induced cardiotoxicity in mice. Altogether, these findings indicate that arginase inhibitors could be further tested as a complementary strategy in multiple myeloma to mitigate adverse cardiac events without compromising antitumor efficacy of proteasome inhibitors.


Subject(s)
Multiple Myeloma , Mice , Animals , Bortezomib/pharmacology , Bortezomib/therapeutic use , Multiple Myeloma/drug therapy , Arginase/metabolism , Cardiotoxicity , Proteasome Inhibitors/pharmacology
2.
Acta Biochim Pol ; 55(3): 499-506, 2008.
Article in English | MEDLINE | ID: mdl-18854874

ABSTRACT

alpha1,6-fucosyltransferase (FUT8) attaches fucose residues via an alpha1,6 linkage to the innermost N-acetylglucosamine residue of N-linked glycans. Glycans with this type of structure are present in GpIIb/GpIIIa complex (CD41a) which is present on megakaryocytes (Mks) and platelets. CD41a is the earliest marker of megakaryocytopoiesis. The aim of this study was to analyse the morphology, phenotype, ploidy level and activity of FUT8 during induced differentiation/maturation of Mk progenitor cells in ex vivo culture. We used SU6656, a selective inhibitor of Src tyrosine kinases, as differentiation-inducing agent for Mks. The addition of SU6656 to the culture system of megakaryocytic progenitors from cord blood CD34(+) cells and Meg-01 cell line induced their maturation towards later stages of Mk differentiation with increased activity of FUT8. We suggest FUT8 as a candidate for an early marker of differentiation and possibly of the ploidy level of Mks. We confirm a special status of FUT8 in megakaryocytopoiesis.


Subject(s)
Fucosyltransferases/metabolism , Indoles/pharmacology , Megakaryocytes/drug effects , Megakaryocytes/enzymology , Sulfonamides/pharmacology , src-Family Kinases/antagonists & inhibitors , Antigens, CD34/metabolism , Cell Differentiation/drug effects , Cell Line , Cells, Cultured , Fetal Blood/cytology , Galactosyltransferases/metabolism , Humans , Megakaryocytes/cytology , Megakaryocytes/immunology , Platelet Membrane Glycoprotein IIb/metabolism , Ploidies , Protein Kinase Inhibitors/pharmacology , Thrombopoiesis/drug effects
3.
Postepy Biochem ; 54(4): 378-83, 2008.
Article in Polish | MEDLINE | ID: mdl-19248584

ABSTRACT

Src family protein tyrosine kinases play key roles in cell morphology, proliferation, motility, and survival in megakaryocytopoiesis. Six of Src family kinases (Fyn, Lyn, Fgr, Hck, Src and Yes), are present in megakaryocytes (Mks). Src kinases are negative factors of megakaryocytopoiesis induced by thrombopoietin. The inhibitors of Src kinases might be useful as agents inducing maturation of Mks. The experiments with inhibitors of Src kinases used in culture of Mk progenitors and potential megakaryocyte cell lines gave new information about the role of Src kinases in the development of Mks. The pyrrolo-pyrimidyne reagents family and highly selective inhibitor, SU6656, are known and used inhibitors of Src kinases. The presence of inhibitor in ex vivo culture of Mk progenitors blocks proliferation and simultaneously induces the changes in cell morphology, phenotype and ploidy level, indicating the maturation of the cells. The inhibitors of Src kinases also might play the therapeutic role. Dasatinib, dual Bcr-Abl/Src kinase inhibitor, is of high activity and induces hematologic and cytogenetic responses in patients with chronic myelogenous leukaemia in blast crisis.


Subject(s)
Megakaryocyte Progenitor Cells/enzymology , Megakaryocytes/metabolism , src-Family Kinases/metabolism , Animals , Cell Proliferation/drug effects , Humans , Indoles/pharmacology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Megakaryocytes/cytology , Sulfonamides/pharmacology , Thrombopoiesis/physiology , Thrombopoietin/metabolism , src-Family Kinases/antagonists & inhibitors
4.
Exp Hematol ; 34(7): 914-25, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16797419

ABSTRACT

OBJECTIVE: The exposure of human umbilical cord blood mononuclear cells devoid of hematopoietic stem cells (HUCB-MNCsCD34-) to defined culture condition promotes their conversion into neural lineage. We have asked the question if observed fate change of HUCB-MNCsCD34- results from direct conversion of hematopoietic precursors into neural-like phenotypes due to expression of overlapping genetic program or, alternatively, these neural phenotypes arise from sequential differentiation of more primitive progenitors (embryonic-like cells) preexisting in HUCB-MNCsCD34- fraction. MATERIALS AND METHODS: HUCB-MNCs negatively selected for CD34 antigens were cultured in vitro up to 14 days. Changes in stem/neural cell genes and proteins were successively evaluated during this period and after evoked neuronal differentiation of cells in the presence of RA or BDNF or cocultured with neonatal rat brain astrocytes. RESULTS: Freshly isolated HUCB-MNCsCD34- expressed pluripotent cell markers: Oct3/4, Sox2, and Rex1 genes. During 24 hours of culture the frequency of Oct3/4 immunopositive cells increased markedly with parallel enlargement of "side population" and CD133+ cell appearance. Concomitantly, cultured cells start to form aggregates and express pro-neural genes, i.e., enhanced Sox2, OTX1, Nestin, GFAP, and NF-200. During the next days of culture immunoreactions for beta-tubulin III, MAP2, GFAP, S100beta, Doublecortin, and GalC were induced with reciprocal lowering of stem cell gene and protein markers. At this stage cells successively adhered to the bottom, dispersed, and decreased proliferation rate (Ki67 expression). Additional treatments with neuromorphogenes or coculturing with rat brain primary culture induced further differentiation of these neural precursors toward more advanced neuronal phenotypes. CONCLUSIONS: HUCB-MNCs(CD34-) fraction contains embryonic-like stem/progenitor cells which increase rapidly but transiently in culture, then differentiate spontaneously after cell aggregate adhesion toward neural lineage. Neurally promoted cells from 10-14 DIV culture acquire three main neural-like phenotypes, i.e., neurons, astrocytes, and oligodendrocytes. In this respect they are promising candidates for experimental treatment of neuronal injury; however, the final proof for conversion of HUCB cells to neural cells can be obtained through transplantation experiments.


Subject(s)
Fetal Blood/cytology , Monocytes/cytology , Neurons/cytology , Stem Cells/chemistry , Animals , Animals, Newborn , Base Sequence , Brain-Derived Neurotrophic Factor/pharmacology , Cell Differentiation/drug effects , Coculture Techniques , DNA Primers , Doublecortin Protein , Humans , Immunohistochemistry , Phenotype , RNA, Messenger/genetics , Rats , Rats, Wistar , Reverse Transcriptase Polymerase Chain Reaction , Tretinoin/pharmacology
5.
Cell Mol Biol Lett ; 9(1): 145-52, 2004.
Article in English | MEDLINE | ID: mdl-15048158

ABSTRACT

alpha1,6-Fucosyltransferase (6FucT, E.C. 2.4.1.68) is one of the enzymes involved in the synthesis of N-linked glycans of the GpIIb/IIIa complex (CD41a) which is present on megakaryocytes (MKs) and platelets. In this study, we examined 6FucT activity in ex vivo cultures of immunoselected cord blood CD34(+) cells grown in a medium promoting megakaryocytopoiesis. Our results show that the activity of 6FucT increased ahead of, and thereafter concomitantly with, cells expressing the CD41a antigen. When the CD41a(+) subpopulation of cells was immunoselected (using anti-CD61 i.e. anti-GpIIIa antibodies), its 6FucT activity increased proportionally to the yield of CD61(+)(+)(+) cells. Taking into account the heavy load of 6FucT in platelets and megakaryocytes, we regard this enzyme as a candidate for the earliest marker of MK-commitment in cultured hematopoietic stem cells. Such a marker should allow an earlier detection and earlier transplantation of patients' own, ex vivo expanded, Mk progenitors.


Subject(s)
Antigens, CD34/immunology , Cell Differentiation/physiology , Fucosyltransferases/metabolism , Galactosyltransferases/metabolism , Megakaryocytes/enzymology , Cells, Cultured , Humans , Integrin beta3/immunology , Megakaryocytes/cytology , Platelet Membrane Glycoprotein IIb/immunology
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