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PubMed2005

[Suppressive effect of high-dose chemotherapy (HDC) on the clonal growth of grafted peripheral blood granulocyte progenitors is reduced 72 hours after completion of HDC].

Hematopoietic stem cells (HSC) transplantations are usually performed 24-48 hours after the end od high-dose chemotherapy (HDC). It is possible, however, that at that time the transplanted HSC can be affected by the administered drugs. We report the results obtained in 30 patients (pts) with hematological malignancies (multiple myeloma - 14, Hodgkin's disease -6, non-Hodgkin's lymphomas -4, chronic myeloid leukemia -6) treated with HDC with peripheral blood stem cell transplantation (PBSCT). The following HDC regimens were applied: melphalan - 14, Dexa-BEAM (dexamethasone, BCNU, etoposide, cytarabine, melphalan) - 10 and BuCy2 (busulfan, cyclophosphamide) - 6. To evaluate the impact of HDC on the growth ability of less /14/ and more /7/ mature CFU-GM, sera were taken directly before cytoreductive chemotherapy, on the last day of HDC (0 day) and on days 1, 2, 3, 4 and 5 after the end of HDC. After melphalan, for CFU-GM/14/ the following results were received: days 0 - 54 +/- 9, 1 - 55 +/- 9, 2 - 68 +/- 12, 3 - 82 +/- 10, 4 - 95 +/- 8,5 - 100 +/- 8% and for CFU-GM/7/: days 0 - 60 +/- 11, 1 - 59 +/- 8, 2 - 72 +/- 11, 3 - 80 +/- 7, 4 - 90 +/- 9, 5 - 105 +/- 7%, determined as a percentage of those obtained before HDC (100%). After Dexa-BEAM, for CFU-GM/14/: days 0 - 45 +/- 13, 1 - 49 +/- 8, 2 - 59 +/- 12, 3 - 85 +/- 15, 4 - 96 +/- 9, 5 - 106 +/- 11%, and for CFU-GM/7/: 0 - 43 +/- 15, 1 - 50 +/- 9, 2 - 63 +/- 11, 3 - 89 +/- 11, 4 - 98 +/- 11, 5 - 110 +/- 8%. In case of BuCy2, for CFU-GM/14/: days 0 - 55 +/- 13, 1 - 67 +/- 7, 2 - 69 +/- 15, 3 - 85 +/- 10, 4 - 103 +/- 12, 5 - 108 +/- 7% and for CFU-GM/7/: days 0 - 50 +/- 12, 1 - 71 +/- 6, 2 - 76 +/- 16, 3 - 98 +/- 9, 4 - 105 +/- 11, 5 - 101 +/- 8%. In all pts PBSCT were infused 72 hours after HDC. The median time to reach granulocytes > 0.5 G/l and >1.0 G/l was 12 (8-17) and 13 (9-18) days, respectively. The recovery of platelets >20.0 G/l and >50. 0 G/l occured after 17 (9-48) and 25 (11-54) days, respectively. We conclude that the suppressive effect of the sera taken on days 0-2 on the CFU-GM growth depends on the HDC-regimen. We have also shown that third day after completion of HDC is the optimal time for the infusion of HSC. The time of hematological reconstituton is related in all investigated pts and independently on the HDC-program (p>0.05).

Adolescent↗
PubMed2005

The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis.

G-CSF is a potent hematopoietic factor that enhances survival and drives differentiation of myeloid lineage cells, resulting in the generation of neutrophilic granulocytes. Here, we show that G-CSF passes the intact blood-brain barrier and reduces infarct volume in 2 different rat models of acute stroke. G-CSF displays strong anti-apoptotic activity in mature neurons and activates multiple cell survival pathways. Both G-CSF and its receptor are widely expressed by neurons in the CNS, and their expression is induced by ischemia, which suggests an autocrine protective signaling mechanism. Surprisingly, the G-CSF receptor was also expressed by adult neural stem cells, and G-CSF induced neuronal differentiation in vitro. G-CSF markedly improved long-term behavioral outcome after cortical ischemia, while stimulating neural progenitor response in vivo, providing a link to functional recovery. Thus, G-CSF is an endogenous ligand in the CNS that has a dual activity beneficial both in counteracting acute neuronal degeneration and contributing to long-term plasticity after cerebral ischemia. We therefore propose G-CSF as a potential new drug for stroke and neurodegenerative diseases.

Animals↗
PubMed1992

Detecting of the minimal residual disease contaminated in peripheral blood stem cell transplantation in the B-cell malignant lymphoma patients.

For sufficient collection of hemopoietic stem cells from peripheral blood for autologous peripheral blood stem cell transplantation (PBSCT), four patients with B-cell-type non-Hodgkin lymphoma (B-NHL) were examined for the appearance of circulating hemopoietic progenitors in blood (PSC) during the hemopoietic recovery phase following marrow ablative therapy in combination with or without administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF). Each patient received only chemotherapy in the first course, and rhG-CSF (1 microgram/kg/day) was administered for 14 consecutive days from the last day of the second chemotherapy. In the second chemotherapy course with rhG-CSF administration, white blood cell (WBC) counts demonstrated two peaks, and the appearance of granulocyte-macrophage precursor cells (CFU-GM) in blood at the maximum level was coincident with the second peak of WBC elevation. Erythroid precursor cells (BFU-E) were also detectable in blood after chemotherapy but the peak level was not enhanced by the use of rhG-CSF. To determine whether the minimal residual disease (MRD) cells were contaminated in PSC corrected from blood, kappa-lambda imaging (KLI) analysis was performed to detect the malignant B-cell population (mBp) before and after chemotherapy. No mBp was found in two of four patients in blood, although three of them were involved with mBp in bone marrow. The presence of mBp was detected in two patients both before and after chemotherapy, even though these cells were hardly detected morphologically, suggesting the necessity of judging for the incidence of contamination of MRD cells when collecting PSCs.

Adult↗
PubMed1988

The effect of low dose rate on recovery of hemopoietic and stromal progenitor cells in gamma-irradiated mouse bone marrow.

Long-term recovery of mouse hemopoietic stem cells (CFU-S and CFU-S per colony), granulocyte-macrophage precursor cells (GM-CFC), and stromal colony-forming units (CFU-F) after doses up to 12.5 Gy was almost complete by 1 year when the dose rate was reduced to 0.0005 Gy/min compared to incomplete recovery after doses up to only 6.5 Gy given at greater than 0.7 Gy/min. This sparing effect of dose rate on long-term hemopoietic recovery is in contrast to the generally reported lack of dependence on dose rate for acute survival of hemopoietic progenitors after doses up to 5 Gy. The present results are compatible with the hypothesis that good recovery of the stroma should be reflected in the long-term recovery of hemopoiesis.

Animals↗
PubMed2006

Tfe3 expression is closely associated to macrophage terminal differentiation of human hematopoietic myeloid precursors.

The MItf-Tfe family of basic helix-loop-helix leucine zipper (bHLH-Zip) transcription factors encodes four family members: MItf, Tfe3, TfeB and TfeC. In vitro, each protein of the family binds DNA in a homo- or heterodimeric form with other family members. Tfe3 is involved in chromosomal translocations recurrent in different tumors and it has been demonstrated, by in vivo studies, that it plays, redundantly with MItf, an important role in the process of osteoclast formation, in particular during the transition from mono-nucleated to multi-nucleated osteoclasts. Since mono-nucleated osteoclasts derive from macrophages we investigated whether Tfe3 might play a role upstream during hematopoietic differentiation. Here we show that Tfe3 is able to induce mono-macrophagic differentiation of U937 cells, in association with a decrease of cell proliferation and an increase of apoptosis. We also show that Tfe3 does not act physiologically during commitment of CD34+ hematopoietic stem cells (HSCs), since it is not able to direct HSCs toward a specific lineage as observed by clonogenic assay, but is a strong actor of terminal differentiation since it allows human primary myeloblasts' maturation toward the macrophage lineage.

Antigens, Differentiation↗
PubMed2006

Src homology 2 domain of overexpressed Lyn kinase is responsible for the acceleration of granulocyte colony-stimulating factor-induced neutrophilic nuclear lobulation.

We have previously shown that the overexpression of a Src family kinase, Lyn, and its kinase-negative form, LynKN, in a granulocyte progenitor cell line, GM-I62M, accelerates neutrophilic nuclear lobulation when the cells are cultured in the presence of granulocyte colony-stimulating factor. In this study, we investigated the role of the Src homology 2 (SH2) and SH3 domains of Lyn in the accelerated induction of nuclear lobulation. In contrast to wild-type Lyn, the overexpression of its SH2 domain mutant did not induce the accelerated nuclear morphological changes, but the overexpressed SH3 domain mutant had the same effects as wild-type Lyn. Therefore, the SH2 domain of Lyn is responsible for the accelerated induction of neutrophilic nuclear lobulation upon G-CSF stimulation.

Animals↗
PubMed2005

Association of post-thaw viable CD34+ cells and CFU-GM with time to hematopoietic engraftment.

In all, 78 peripheral hematopoietic progenitor cell collections from 52 patients were evaluated using our previously published validated post-thaw assays at the time of collection and following transplantation by assessment of viable CD34(+) cells, and granulocyte-macrophage colony-forming units (CFU-GM) cryopreserved in quality control vials. The median (range) post-thaw recovery of viable CD34(+) cells and CFU-GM was 66.4% (36.1-93.6%) and 63.0% (28.6-85.7%), respectively, which did not show significant correlation with the engraftment of either neutrophils (P=0.136 and 0.417, respectively) or platelets (P=0.88 and 0.126, respectively). However, the reinfused viable CD34(+) cells/kg of patient weight pre- or post-cryopreservation showed significant correlation to engraftment of neutrophils (P=0.0001 and 0.001, respectively) and platelets (P=0.023 and 0.010, respectively), whereas CFU-GM pre- or post-cryopreservation was significantly correlated to neutrophils (P=0.011 and 0.007, respectively) but not to platelets (P=0.112 and 0.100, respectively). The results show that post-cryopreservation assessment of viable CD34(+) cells or CFU-GM is as reliable a predictor of rapid engraftment as that of pre-cryopreservation measures. Therefore, the post-cryopreservation number of viable CD34(+) cells or CFU-GM should be used to eliminate the risks of unforeseen cell loss that could occur during cryopreservation or long-term storage.

Adult↗
PubMed2004

Annexin A2 expression during cellular differentiation in myeloid cell lines.

Annexin A2 is a calcium-dependent, phospholipid-binding protein found on many cell types. It consists of a short hydrophobic tail (Ser(2)-Asn(32)), which dictates its function, and a core domain (Phe(33)-Asp(339)), which is involved in phospholipid binding. Annexin A2 has been implicated in a number of biochemical processes, including cell proliferation, foetal immune tolerance, ion-channel activation, cell-cell interactions and the bridging of membranes. Annexin A2 is reported to be a powerful activator of plasminogen and, therefore, is implicated in many normal and pathological processes such as haemostasis and metastasis. Myeloid cell lines are used, extensively, to study many aspects of cellular proliferation, differentiation and function. In the present study, we have used flow cytometry and real-time PCR to investigate the role of annexin A2 expression in the proliferation and differentiation of a number of myeloid cell lines. The results demonstrated that annexin A2 expression was affected when the cells were induced to differentiate by stimulation with all-trans-retinoic acid. Annexin A2 may, therefore, be an important player in cellular differentiation and its disorders.

Animals↗
PubMed2003

CUL-4A stimulates ubiquitylation and degradation of the HOXA9 homeodomain protein.

The HOXA9 homeodomain protein is a key regulator of hematopoiesis and embryonic development. HOXA9 is expressed in primitive hematopoietic cells, and its prompt downregulation is associated with myelocytic maturation. Although transcriptional inactivation of HOXA9 during hematopoietic differentiation has been established, little is known about the biochemical mechanisms underlying the subsequent removal of HOXA9 protein. Here we report that the CUL-4A ubiquitylation machinery controls the stability of HOXA9 by promoting its ubiquitylation and proteasome-dependent degradation. The homeodomain of HOXA9 is responsible for CUL-4A-mediated degradation. Interfering CUL-4A biosynthesis by ectopic expression or by RNA-mediated interference resulted in alterations of the steady-state levels of HOXA9, mirrored by impairment of the ability of 32D myeloid progenitor cells to undergo proper terminal differentiation into granulocytes. These results revealed a novel regulatory mechanism of hematopoiesis by ubiquitin-dependent proteolysis.

Cell Differentiation↗
PubMed2005

The role of transcriptional coactivator TRAP220 in myelomonocytic differentiation.

The TRAP220 subunit of the thyroid hormone receptor-associated polypeptide transcription coactivator complex (TRAP/Mediator complex), mammalian counterpart of the yeast Mediator complex, is proposed to act on a variety of major and specific biological events through physical interactions with nuclear receptors. The vitamin D receptor (VDR) and retinoic acid receptor (RAR), coupled with retinoid X receptor (RXR), are nuclear receptors which have important roles for monopoiesis and granulopoiesis, respectively. In this study, we present the functional role of TRAP220 in nuclear receptor-mediated monopoiesis and granulopoiesis. The mouse Trap220(-/-) yolk sac hematopoietic progenitor cells were resistant to 1,25-dihydroxyvitamin D(3)-stimulated differentiation into monocytes/macrophages. Furthermore, flow cytometric analyses showed that HL-60 cells, human promyelocytic leukemia cell line, wherein TRAP220 was down-regulated, did not differentiate efficiently into monocytes and granulocytes by stimulation with 1,25-dihydroxyvitamin D(3) and all-trans retinoic acid, correspondingly. The expression of direct target genes of VDR or RAR, as well as the differentiation marker genes, was low in the knockdown cells. These results indicated a crucial role of TRAP220 in the optimal VDR- and RAR-mediated myelomonocytic differentiation processes in mammalian hematopoiesis.

Animals↗
PubMed2003

Alpha-defensin expression during myelopoiesis: identification of cis and trans elements that regulate expression of NP-3 in rat promyelocytes.

Alpha-defensins are antimicrobial peptides that contribute to innate-immune functions of neutrophils and intestinal Paneth cells. Transcription of alpha-defensin genes occurs early in neutrophilic myelopoeisis. To examine the mechanisms that regulate alpha-defensin gene expression, we analyzed transcription of rat neutrophil alpha-defensin NP-3 in D4 cells, a subclone of the promyelocytic cell line IPC-81. Northern blot analysis showed that D4 cells express fivefold higher levels of alpha-defensin mRNA than the parental cell line in a manner relatively independent of passage number. Increased levels of steady-state mRNA in D4 cells correlated with markedly elevated peptide levels detected by immunocytochemical staining. To identify the cis-acting DNA elements involved in tissue-specific expression, D4 cells were transfected with luciferase reporter constructs containing NP-3 gene 5'-flanking sequences. Analyses of transfected D4 cells demonstrated that the proximal 87 base pair (bp) sequence contained cis-acting DNA elements necessary for optimal promoter activity. Mutational analyses within the 87-bp region suggested the involvement of the CAAT box and a putative polyoma enhancer-binding protein 2/core-binding factor (PEBP2/CBF) site in defensin gene transcription. Transient transfection analyses using tandem repeats of oligonucleotides containing these sequences demonstrated that proximity of the CAAT box and PEBP2/CBF site was important for defensin promoter activity. Electrophoretic mobility shift assays indicated that PEBP2/CBF or a PEBP2/CBF-related protein was involved in a specific protein-DNA interaction occurring within a DNA fragment containing the CAAT and PEBP2/CBF sequences. These data identify functional trans- and cis-elements that regulate rat defensin gene expression in high defensin-expressing promyelocytic cells.

Animals↗
PubMed2004

L-selectin and chemotaxis throughout bone marrow granulocyte maturation in the bovine.

Polymorphonuclear neutrophilic leukocytes (PMNL) play a pivotal role during inflammation. Bone marrow (BM) reserves are depleted as cells are released into circulation for recruitment to infection sites. Expression of L-selectin on the cell membrane allows neutrophils to roll along the activated endothelium. Whereas mechanisms leading to recruitment to infection sites are well established, expression of BM adhesion molecules in cows is limited. In this study, we assessed L-selectin expression and chemotactic response to zymosan-activated serum (ZAS) in bovine BM cells and in circulating neutrophils. Isolated blood PMNL and BM cells were used from 9 dairy cows, for quantifying L-selectin expression using flow cytometry, and from 12 dairy cows for chemotaxis studies. All granulocytic maturation stages expressed L-selectin. The percentage of cells fluorescing increased significantly in BM band and mature granulocytes and reached maximal expression on circulating neutrophils. Bone marrow band and segmented cells showed the highest L-selectin density. Chemotaxis through micropore filters in response to zymosan-activated fetal bovine serum was first observed in the myelocytic and metamyelocytic stages, and it increased with maturation and release into the blood stream. From these results, we conclude that L-selectin expression varies among stages of granulocytic maturation within the BM and differs from circulating PMNL. Further, BM cells are capable of migration starting at the metamyelocytic stage, and compared with BM cells, circulating neutrophils are more chemotactively active.

Animals↗