scholarly journals Antiapoptotic activity of Stat5 required during terminal stages of myeloid differentiation

2000 ◽  
Vol 14 (2) ◽  
pp. 232-244
Author(s):  
Matthias Kieslinger ◽  
Irina Woldman ◽  
Richard Moriggl ◽  
Johannes Hofmann ◽  
Jean-Christophe Marine ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Strong Increase ◽  
Main Function ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Deficient Mice ◽  
Marrow Cells

Stat5 is activated by multiple receptors of hematopoietic cytokines. To study its role during hematopoiesis, we have generated primary chicken myeloblasts expressing different dominant-negative (dn) alleles of Stat5. This caused a striking inability to generate mature cells, due to massive apoptosis during differentiation. Bcl-2 was able to rescue differentiating cells expressing dnStat5 from apoptosis, suggesting that during cytokine-dependent differentiation the main function of the protein is to ensure cell survival. Our findings with dnStat5-expressing chicken myeloblasts were confirmed with primary hematopoietic cells from Stat5a/Stat5b-deficient mice. Bone marrow cells from these animals displayed a strong increase in apoptotic cell death during GM-CSF-dependent functional maturation in vitro. The antiapoptotic protein Bcl-x was induced by GM-CSF and IL-3 in a Stat5-dependent fashion. Ectopic expression of Bcl-x rescued Stat5-deficient bone marrow cells from apoptosis, indicating that Stat5 promotes the survival of myeloid progenitor cells through its ability to induce transcription of the bcl-x gene. Finally, the recruitment of myeloid cells to inflammatory sites was found strongly impeded in Stat5-deficient mice. Taken together, our findings suggest that Stat5 may promote cytokine-dependent survival and proliferation of differentiating myeloid progenitor cells in stress or pathological situations, such as inflammation.

Myeloid Progenitor Cells from Gadd45a and Gadd45b-Deficient Mice Are Sensitized to Genotoxic-Stress Induced Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4239-4239
Author(s):  
Mamta Gupta ◽  
Shiv K. Gupta ◽  
Arthur G. Balliet ◽  
Barbara Hoffman ◽  
Dan A. Lieberman
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Genotoxic Stress ◽  
Wild Type ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Induced Apoptosis ◽  
Deficient Mice ◽  
Marrow Cells

Abstract GADD45 (Growth arrest and DNA damge) regulates cell growth following exposure to diverse stimuli. It has been shown that, mice lacking the gadd45a gene exhibit genomic instability and increased carcinogenesis, but the exact role of the gadd45 family genes still remains unclear. In this study we have aimed at determining the effect of gadd45a or gadd45b deficiency on the response of bone marrow derived myeloid cells to genotoxic stress agents by using gadd45a or gadd45b null mice. We have found that myeloid progenitor cells from gadd45a or gadd45b-null mice are more sensitive to ultraviolet-radiation (UV), VP-16 or daunorubicin induced apoptosis. Introduction of wild-type gadd45 into gadd45-deficient bone marrow cells restored the wild-type apoptotic phenotype. In-vitro colony formation following stress responses has shown that bone marrow cells from gadd45a or gadd45b-deficient mice have a decreased ability to form haematopoetic colonies. Gadd45a or gadd45b-deficient bone marrow cells also displayed defective G2/M cell cycle checkpoint following exposure to either UV and V-16 but were still able to undergo G2/M arrest following exposure to daunorubicin, indicating the existence of different G2/M checkpoints in response to these anticancer agents. Taken together these findings identify gadd45a or gadd45b as anti-apoptotic gene(s), and suggests that the absence of gadd45a or gadd45b results in higher susceptibility of haematopoetic cells to UV radiation and certain anticancer drugs.

scholarly journals Detection of the target progenitor cells of granulomonopoietic enhancing activity

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 495-500
Author(s):  
SY Wang ◽  
YM Li ◽  
LY Chen ◽  
RC Wang ◽  
CK Lin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Soft Agar ◽  
Velocity Sedimentation ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Maturation Factor ◽  
Myeloid Progenitor Cells ◽  
Marrow Cells

Macrophage-derived granulomonopoietic enhancing activity (GM-EA) is a novel mediator that amplifies colony formation of myeloid progenitor cells (CFU-GM) in conjunction with colony-stimulating factors (CSFs), and is distinct from other hematopoietic synergizing factors such as interleukin (IL)-1, IL-4, and IL-6. In the present study, we try to ascertain whether or not there is a GM-EA-specific responsive myeloid progenitor cell population. Human bone marrow cells deleted of adherent cells and T lymphocytes were separated by velocity sedimentation into three subpopulations with respective sedimentation rates (millimeters per hour) of 7.4 +/- 0.4, 6.0 +/- 0.6, and 4.7 +/- 0.3. These subpopulations corresponded to the day 7 CFU-GM, day 14 CFU-GM, and the earlier myeloid progenitor cells, pre-CFU-GM, respectively. Pre-CFU-GM failed to respond to the colony-inducing effect of GM-CSF but could be stimulated by GM-EA alone to generate small clusters (5 to 25 cells) in soft agar after 14 days of incubation. Correspondingly, suspension preculture of the fractionated bone marrow cells also showed that only the progenitor cells with low sedimentation rate (4.7 mm/h) could be activated by GM-EA to generate CFU-GM. Taken together, our results suggest that the specific target cell of GM-EA is the pre-CFU-GM, and that GM-EA acts on these cells as a growth/maturation factor, but on the day 7 and day 14 CFU-GM as a synergistic growth factor.

scholarly journals Detection of the target progenitor cells of granulomonopoietic enhancing activity

Blood ◽  
1990 ◽  
Vol 76 (3) ◽  
pp. 495-500 ◽  
Author(s):  
SY Wang ◽  
YM Li ◽  
LY Chen ◽  
RC Wang ◽  
CK Lin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Soft Agar ◽  
Velocity Sedimentation ◽  
Gm Csf ◽  
Myeloid Progenitor ◽  
Maturation Factor ◽  
Myeloid Progenitor Cells ◽  
Marrow Cells

Abstract Macrophage-derived granulomonopoietic enhancing activity (GM-EA) is a novel mediator that amplifies colony formation of myeloid progenitor cells (CFU-GM) in conjunction with colony-stimulating factors (CSFs), and is distinct from other hematopoietic synergizing factors such as interleukin (IL)-1, IL-4, and IL-6. In the present study, we try to ascertain whether or not there is a GM-EA-specific responsive myeloid progenitor cell population. Human bone marrow cells deleted of adherent cells and T lymphocytes were separated by velocity sedimentation into three subpopulations with respective sedimentation rates (millimeters per hour) of 7.4 +/- 0.4, 6.0 +/- 0.6, and 4.7 +/- 0.3. These subpopulations corresponded to the day 7 CFU-GM, day 14 CFU-GM, and the earlier myeloid progenitor cells, pre-CFU-GM, respectively. Pre-CFU-GM failed to respond to the colony-inducing effect of GM-CSF but could be stimulated by GM-EA alone to generate small clusters (5 to 25 cells) in soft agar after 14 days of incubation. Correspondingly, suspension preculture of the fractionated bone marrow cells also showed that only the progenitor cells with low sedimentation rate (4.7 mm/h) could be activated by GM-EA to generate CFU-GM. Taken together, our results suggest that the specific target cell of GM-EA is the pre-CFU-GM, and that GM-EA acts on these cells as a growth/maturation factor, but on the day 7 and day 14 CFU-GM as a synergistic growth factor.

scholarly journals Abnormal responses of myeloid progenitor cells to recombinant human colony-stimulating factors in congenital neutropenia

Blood ◽  
1990 ◽  
Vol 75 (11) ◽  
pp. 2143-2149 ◽  
Author(s):  
M Kobayashi ◽  
C Yumiba ◽  
Y Kawaguchi ◽  
Y Tanaka ◽  
K Ueda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Normal Subjects ◽  
Inhibitory Effect ◽  
Congenital Neutropenia ◽  
Agar Culture ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Marrow Cells

Abstract The effects of recombinant human interleukin-3 (IL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) in semisolid agar culture were studied in two patients with Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from patients was significantly reduced in response to various concentrations of either IL-3 or G-CSF alone, compared with that from normal subjects. There was no inhibitory effect of bone marrow cells from patients on normal CFU-C formation supported by IL-3 or G-CSF. However, the simultaneous stimulation with IL-3 and G- CSF induced the increase of CFU-C formation in patients with congenital neutropenia. Furthermore, CFU-C growth in both patients was supported when bone marrow cells were preincubated with IL-3 in liquid culture followed by the stimulation with G-CSF in semisolid agar culture. In contrast, that was not supported by the preincubation with G-CSF and the subsequent stimulation with IL-3. This evidence suggests that the hematopoietic progenitor cells in patients with congenital neutropenia have the potential for developing CFU-C in the combined stimulation with IL-3 and G-CSF, and that this growth may be dependent on the priming of IL-3 followed by the stimulation with G-CSF. The level of mature neutrophils in peripheral blood was not fully restored to normal levels by the daily administration of G-CSF in doses of 100 to 200 micrograms/m2 of body surface area for 20 to 25 days in both patients. These observations raise the possibility that the combination of IL-3 and G-CSF might have a potential role for the increase of neutrophil counts in patients with congenital neutropenia.

scholarly journals Abnormal responses of myeloid progenitor cells to recombinant human colony-stimulating factors in congenital neutropenia

Blood ◽  
1990 ◽  
Vol 75 (11) ◽  
pp. 2143-2149 ◽  
Author(s):  
M Kobayashi ◽  
C Yumiba ◽  
Y Kawaguchi ◽  
Y Tanaka ◽  
K Ueda ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Bone Marrow Cells ◽  
Normal Subjects ◽  
Inhibitory Effect ◽  
Congenital Neutropenia ◽  
Agar Culture ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Marrow Cells

The effects of recombinant human interleukin-3 (IL-3) and recombinant human granulocyte colony-stimulating factor (G-CSF) on the growth of myeloid progenitor cells (CFU-C) in semisolid agar culture were studied in two patients with Kostmann-type congenital neutropenia. CFU-C growth in bone marrow cells from patients was significantly reduced in response to various concentrations of either IL-3 or G-CSF alone, compared with that from normal subjects. There was no inhibitory effect of bone marrow cells from patients on normal CFU-C formation supported by IL-3 or G-CSF. However, the simultaneous stimulation with IL-3 and G- CSF induced the increase of CFU-C formation in patients with congenital neutropenia. Furthermore, CFU-C growth in both patients was supported when bone marrow cells were preincubated with IL-3 in liquid culture followed by the stimulation with G-CSF in semisolid agar culture. In contrast, that was not supported by the preincubation with G-CSF and the subsequent stimulation with IL-3. This evidence suggests that the hematopoietic progenitor cells in patients with congenital neutropenia have the potential for developing CFU-C in the combined stimulation with IL-3 and G-CSF, and that this growth may be dependent on the priming of IL-3 followed by the stimulation with G-CSF. The level of mature neutrophils in peripheral blood was not fully restored to normal levels by the daily administration of G-CSF in doses of 100 to 200 micrograms/m2 of body surface area for 20 to 25 days in both patients. These observations raise the possibility that the combination of IL-3 and G-CSF might have a potential role for the increase of neutrophil counts in patients with congenital neutropenia.

Myc Induces Acute Myeloid Leukemia by Conferring Self-Renewal Activity to Committed Myeloid Progenitor Cells That Resist Apoptosis Via Endogenous Mcl-1.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2634-2634
Author(s):  
Hui Luo ◽  
Jennifer A. Cain ◽  
AnnaLynn Molitoris ◽  
Joseph Opferman ◽  
Michael H. Tomasson
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Median Survival ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Ectopic Expression ◽  
Hematopoietic Stem ◽  
Myeloid Progenitor ◽  
Myeloid Progenitor Cells ◽  
Induced Apoptosis

Abstract Ectopic expression of Myc in most primary cell types induces apoptosis, and cancer development typically requires additional, anti-apoptotic mutations. We reported previously that ectopic expression of Myc in unfractionated murine bone marrow cells induced rapid onset acute myeloid leukemia (AML) without detectable anti-apoptotic mutations. We hypothesized that AML developed in our model because a subset of normal primary bone marrow cells were inherently resistant to Myc-induced apoptosis. Consistent with this model, seven days of Myc activation in the bone marrow of mice caused the reduction of B-lineage cells while at the same time inducing the expansion of myeloid lineage cells. We sought to determine the mechanism by which myeloid progenitor cells evaded Myc-induced apoptosis, and found that Myc-induced AML cells exhibited a distinct profile of pro- and anti-apoptotic proteins, including high levels of the anti-apoptotic Bcl-2 family member Mcl-1. To prioritize apoptosis genes, we examined AML patient microarray data and found MCL1 to be uniformly expressed at high levels in human AML (94/94, 100%). We used Mcl1 heterozygous mice (Mcl1F/null) as bone marrow donors for transduction-transplantation experiments and found that, compared with Mcl1 wild-type (median survival=60 days), haploinsufficiency for Mcl1 completely protected mice from Myc-induced AML (median survival not reached). Mice transplanted with Mcl1F/null cells co-expressing Myc and Bcl2 succumbed rapidly to disease (median survival 25 days). In wild-type mice, defined hematopoietic stem and myeloid progenitor cell populations were not significantly increased by Myc activation. However, Myc transduction conferred serial replating ability to sorted hematopoietic stem and progenitor cells including lineage-committed (Lin+Kit+) progenitors cells. These data demonstrate a critical role for Mcl1 in our AML model and suggest that dysregulation of MYC in MCL1-expressing progenitor cells may mediate AML pathogenesis in humans.

EC-18 (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) Exhibits the Immune Regulatory Role through HSC Differentiation of Bone Marrow Cells in Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4757-4757
Author(s):  
Ha-Reum Lee ◽  
Su-Hyun Shin ◽  
Nina Yoo ◽  
Sun Young Yoon ◽  
Myung-Hwan Kim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Cell Population ◽  
Progenitor Cell ◽  
Bone Marrow Cells ◽  
Dependent Manner ◽  
Deer Antler ◽  
Myeloid Progenitor ◽  
Progenitor Cell Population ◽  
Marrow Cells

Abstract EC-18 (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) was originally isolated as a component of an extract from deer antler is traditionally used as an oriental medicine for hematopoiesis. A trace of MADG (monoacetyldiacylglyceride) could be detected in the deer antler, animal tissue, seed oils and bovine udder, which is identical to its natural source of MADG was chemically synthesized with glycerol, palmitic acid and linoleic acid. Previous study described that EC-18 has effect on the proliferation of hematopoietic stem cells (HSCs) (Biol. Pharm. Bull. 2004, 27(7): 1121-1125). Successively, we investigated the biological role of EC-18 in the differentiation of bone marrow cells into progenitor cell population in mice. EC-18 was administered daily for 1, 5 and 15 days to 6 week-aged C57BL/6 mice. Bone marrow cells of EC-18 administrated mice were collected from femurs and tibiae. Cell population was analyzed by FACs. As results, the total number of bone marrow cells was increased in EC-18 administered mice. To identify hematopoietic lineage cell population, we used lineage cocktail antibody kit including anti-mouse CD3, CD11b, CD45R, Gr-1 and TER-119. The lineages negative population contains HSCs which can self-renew and generate into all lineages of the hematopoietic system. The lineage negative cells significantly increased in time dependent manner in the EC-18-daily administrated mice. Cell population between myeloid progenitor (Lin- Sca1- Kit+) and common lymphoid progenitors (Lin- Sca1+ Kit+ IL-7R-α+) were analyzed using the antibody for Sca-1, c-Kit, IL-7R-α. The data showed that the population of myeloid progenitor cells was markedly increased rather than common lymphoid progenitor cells. In myeloid progenitor cell population, the cell population of megakaryocyte/erythrocyte progenitors (MEP) and granulocyte-monocyte progenitors (GMP) also elevated significantly. Taken together, EC-18 may have a potential role in the HSC differentiation and could be used as a therapeutic agent for anemia and neutropenia. Disclosures No relevant conflicts of interest to declare.

Divergent effects of interleukin-4 (IL-4) on the granulocyte colony- stimulating factor and IL-3-supported myeloid colony formation from normal and leukemic bone marrow cells

Blood ◽  
1990 ◽  
Vol 75 (3) ◽  
pp. 633-637
Author(s):  
E Vellenga ◽  
JT de Wolf ◽  
JA Beentjes ◽  
MT Esselink ◽  
JW Smit ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Interleukin 4 ◽  
Myeloid Progenitor ◽  
Accessory Cells ◽  
Myeloid Progenitor Cells ◽  
Morphologic Analysis ◽  
Cell Fractions ◽  
Marrow Cells

Human recombinant interleukin-4 (IL-4) was studied for its effects on myeloid progenitor cells from normal and leukemic bone marrow cells in the presence and absence of additional growth factors. IL-4 itself did not support myeloid cluster or colony formation (CFU-GM). However, cultures supplied with IL-4 (300 U/mL) and IL-3 demonstrated a significant decline in myeloid colony numbers (CFU-GM) compared with the effects of IL-3 alone: (48 +/- 27 v 88 +/- 27 CFU-GM/10(5) MNC). In contrast, IL-4 augmented the G-CSF-supported CFU-GM: (80 +/- 31 v 148 +/- 52 CFU-GM/10(5) MNC). The effects of IL-4 were not mediated by accessory cells because similar results were obtained with and without T-cell, B-cell, or adherent depleted cell fractions. Morphologic analysis of clusters (day 7) and the colonies (day 14) demonstrated that IL-4 enhanced myeloid colony formation in the presence of G-CSF, whereas the cultures supplied with IL-3 and IL-4 did not show a lineage- restricted decline of CFU-GM. A heterogeneity in growth response was observed in the leukemic counterpart. With the 3H-thymidine proliferation assay, IL-4 augmented the G-CSF-induced proliferation of acute myeloid leukemic (AML) cells in 4 of the 12 cases, while the IL-3- supported proliferation was antagonized in 3 of the 12 cases. In the blast colony assay, IL-4 suppressed the IL-3-supported AML-CFU in the majority of cases, but enhanced the G-CSF stimulated AML-CFU in 3 of 6 cases. These data demonstrate divergent effects of IL-4 on the normal myeloid progenitor cell in the presence of IL-3 or G-CSF, while a variability in responsiveness is observed in the leukemic counterpart.

scholarly journals Interleukin 6 is a permissive factor for monocytic colony formation by human hematopoietic progenitor cells.

1992 ◽  
Vol 175 (4) ◽  
pp. 1151-1154 ◽  
Author(s):  
J H Jansen ◽  
J C Kluin-Nelemans ◽  
J Van Damme ◽  
G J Wientjens ◽  
R Willemze ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Progenitor Cells ◽  
Interleukin 6 ◽  
Colony Formation ◽  
Bone Marrow Cells ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Marrow Cells

Since monocytes and macrophages that arise during the culture of bone marrow progenitor cells are potential sources of interleukin 6 (IL-6), we investigated whether auto- or paracrine production of this factor is involved in colony formation by normal hematopoietic progenitor cells. We added a polyclonal anti-IL-6 antiserum and a monoclonal anti-IL-6 antibody to cultures of monocyte- and T cell-depleted bone marrow cells. Colony formation was stimulated with granulocyte/monocyte-colony-stimulating factor (GM-CSF), monocyte-CSF, or IL-3. Addition of anti-IL-6 antibody resulted in decreased numbers of monocytic colonies to 40-50% of control values, whereas the numbers of granulocytic colonies were not altered. The inhibitory effect was preserved in cultures of CD34(+)-enriched bone marrow cells. As a second approach, we added a monoclonal antibody directed against the IL-6 receptor to cultures of monocyte- and T cell-depleted bone marrow cells. This antibody almost completely inhibited the growth of monocytic colonies, again without decreasing the number of granulocytic colonies. Finally, the importance of IL-6 in monocytopoiesis was demonstrated in serum-deprived bone marrow cultures: addition of exogenous IL-6 to cultures stimulated with GM-CSF resulted in increased numbers of monocytic colonies. Our results indicate that the permissive presence of IL-6 is required for optimal monocytic colony formation by bone marrow progenitor cells.

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