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Suppression of erythroid but not megakaryocytic differentiation of human K562 erythroleukemic cells by Notch-1

JOURNAL OF BIOLOGICAL CHEMISTRY 2000年第26期275卷 19676-19684页

作者： Lam, LT Ronchini, C Norton, J Capobianco, AJ Bresnick, EH Univ Wisconsin Sch Med Dept Pharmacol Mol & Cellular Pharmacol Program Madison WI 53706 USA Univ Cincinnati Coll Med Dept Mol Genet Biochem & Microbiol Cincinnati OH 45267 USA

The Notch signal transduction pathway is a highly conserved regulatory system that controls multiple developmental processes. We have established an erythroleukemia cell model to study how Notch regulates cell fate and erythroleukemic cell differentiation. K562 and HEL cells expressed the Notch-1 receptor and the Notch ligand Jagged-1. The stable expression of the constitutively active intracellular domain of Notch-1 (NIC-1) in K562 cells inhibited erythroid without affecting megakaryocytic maturation. Expression of antisense Notch-1 induced spontaneous erythroid maturation. Suppression of erythroid maturation by NIC-1 did not result from down-regulation of GATA-1 and TAL-1, transcription factors necessary for erythroid differentiation. Microarray gene expression analysis identified genes activated during erythroid maturation, and NIC-1 disrupted the maturation-dependent changes in the expression of these genes. These results show that NIC-1 alters the pattern of gene expression in K562 cells leading to a block in erythroid maturation and therefore suggest that Notch signaling may control the developmental potential of normal and malignant erythroid progenitor cells.

关键词：碱性螺旋-环-螺旋转录因子类联苯胺类/药理学印迹法蛋白质钙结合蛋白质类细胞分化/生理学 DNA 反义/代谢 DNA结合蛋白质类/代谢剂量效应关系药物减量调节红细胞/细胞学红系细胞特异性DNA结合因子类 GATA1转录因子氯化血红素/药理学胞间信号肽类和蛋白质类 K562细胞白血病幼红细胞急性/代谢配体巨核细胞/细胞学膜蛋白质类/生物合成膜蛋白质类/代谢膜蛋白质类/生理学寡核苷酸序列分析质粒蛋白质生物合成蛋白质类/代谢原癌基因蛋白质类 RNA 信使/代谢受体 Notch1 受体细胞表面逆转录病毒科/代谢信号传导时间因素转录因子/代谢转染肿瘤细胞培养的人类

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Collagen or collagen-related peptide cause (Ca²⁺)_i elevation and increased tyrosine phosphorylation in human megakaryocytes

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THROMBOSIS AND HAEMOSTASIS 1999年第3期82卷 1153-1159页

作者： Mountford, JC Melford, SK Bunce, CM Gibbins, J Watson, SP Univ Birmingham Queen Elizabeth Med Ctr Dept Med Birmingham B15 2TH W Midlands England Univ Oxford Dept Pharmacol Oxford England Univ Reading Sch Anim & Microbial Sci Reading RG6 2AJ Berks England

Since megakaryocytes are the cellular precursors of platelets we have investigated whether they share responses to platelet agonists, in particular collagen. Although previous studies have reported responses to thrombin in non-human megakaryocytes, through studies of single cell calcium responses and protein tyrosine-phosphorylation we demonstrate for the first time that both isolated human megakaryocytes and CD41/61-positive megakaryocytes derived in culture from CD34+ cells share responses to the platelet agonists collagen, collagen-related peptide and thrombin. The responses to either collagen or CRP were seen only in the most mature megakaryocytes and not in megakaryocyte-like cell lines, suggesting that the response to collagen is a characteristic developed late during megakaryocyte differentiation. Those primary cells offer the opportunity to use many molecular and cellular techniques to study and manipulate signalling events in response to platelet receptor agonists, which cannot be performed in the small, anucleate platelet itself.

关键词：抗原 CD34/血液钙/代谢细胞分化细胞系胶原/药理学胎血/细胞学细胞内液/药物作用细胞内液/代谢巨核细胞/细胞学巨核细胞/药物作用巨核细胞/代谢磷酰化酪氨酸/代谢人类婴儿新生

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In vitro infection of megakaryocytes and their precursors by human cytomegalovirus

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BLOOD 2000年第2期95卷 487-493页

作者： Crapnell, K Zanjani, ED Chaudhuri, A Ascensao, JL St Jeor, S Maciejewski, JP Univ Nevada Sch Med Dept Cellular & Mol Biol Reno NV 89557 USA Univ Nevada Sch Med Dept Internal Med Reno NV 89557 USA Univ Nevada Sch Med Dept Microbiol Reno NV 89557 USA

Apart from congenital human cytomegalovirus(HCMV) infection, manifest HCMV disease occurs primarily in immunocompromised patients. In allogeneic bone marrow transplantation, HCMV is frequently associated with graft failure and cytopenias involving all hematopoietic lineages, but thrombocytopenia is the most commonly reported hematologic complication. The authors hypothesized that megakaryocytes (MK) may be a specific target for HCMV, Although the susceptibility of immature hematopoietic progenitors cells to HCMV has been established, a productive viral life cycle has only been linked to myelomonocytic maturation. The authors investigated whether HCMV can also infect MK and impair their function. They demonstrated that HCMV did not affect the thrombopoietin (TPO)-driven proliferation of CD34(+) cells until MK maturation occurred. MK challenged with HCMV showed a 50% more rapid loss of viability than mock-infected cells. MK and their early precursors were clearly shown to be susceptible to HCMV in vitro, as evidenced by the presence of HCMV in magnetic column-purified CD42(+) MK and P-color fluorescent staining with antibodies directed against CD42a and HCMV pp65 antigen, These findings were confirmed by the infection of MK with a laboratory strain of HCMV containing the beta-galactosidase (beta-gal) gene. Using chromogenic beta-gal substrates, HCMV was detected during MK differentiation of infected CD34(+) cells and after infection of fully differentiated MK, Production of infectious virus was observed in cultures infected MK, suggesting that HCMV can complete its life cycle. These results demonstrate that MK are susceptible to HCMV infection and that direct infection of these cells in vivo may contribute to the thrombocytopenia observed in patients infected with HCMV. (Blood. 2000;95:487-493) (C) 2000 by The American Society of Hematology.

关键词：抗原 CD/分析抗原 CD34/分析骨髓细胞/细胞学细胞分裂细胞分离/方法细胞培养的巨细胞病毒/遗传学巨细胞病毒/致病力巨细胞病毒/生理学 DNA 病毒/分析造血干细胞/细胞学造血干细胞/生理学造血干细胞/病毒学生命周期各时期巨核细胞/细胞学巨核细胞/生理学巨核细胞/病毒学聚合酶链反应重组蛋白质类/生物合成转染病毒蛋白质类/分析 β半乳糖苷酶类/生物合成 β半乳糖苷酶类/遗传学人类

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Induction of megakaryocytic differentiation in primary human erythroblasts -: A physiological basis for leukemic lineage plasticity

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AMERICAN JOURNAL OF PATHOLOGY 2001年第4期158卷 1191-1198页

作者： Goldfarb, AN Wong, DY Racke, FK Univ Virginia Ctr Hlth Sci Dept Pathol Charlottesville VA 22908 USA Johns Hopkins Med Inst Dept Pathol Baltimore MD USA

In myelodysplasias and acute myeloid leukemias, abnormalities in erythroid development often parallel abnormalities in megakaryocytic development. Erythroleukemic cells in particular have been shown to possess the potential to undergo megakaryocytic differentiation in response to a variety of stimuli. Whether or not such lineage plasticity occurs as a consequence of the leukemic phenotype has not previously been addressed. In this study, highly purified primary human erythroid progenitors were subjected to stimuli known to induce megakaryocytic differentiation in erythroleukemic cells. Remarkably, the primary erythroid progenitors rapidly responded with morphological and immunophenotypic evidence of megakaryocytic differentiation, equivalent to that seen in erythroleukemic cells. Even erythroblasts expressing high levels of hemoglobin manifested partial megakaryocytic differentiation. These results indicate that the lineage plasticity observed in erythroleukemic cells reflects an intrinsic property of cells in the erythroid lineage rather than an epiphenomenon of leukemic transformation.

关键词：细胞分化细胞分离幼红细胞/细胞学胎血/细胞学白血病/病理学巨核细胞/细胞学肿瘤细胞培养的人类

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Biologic and structural differences of thrombopoietic growth factors

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SEMINARS IN HEMATOLOGY 2000年第2期37卷 19-27页

作者： Begley, CG Basser, RL Western Australian Inst Med Res Perth WA 6000 Australia Ctr Dev Canc Therapeut Parkville Vic Australia Royal Melbourne Hosp Dept Clin Haematol & Med Oncol Melbourne Vic Australia Royal Melbourne Hosp Rotary Bone Marrow Res Labs Melbourne Vic Australia Walter & Eliza Hall Inst Med Res Parkville Vic Australia Ludwig Inst Canc Res CH-1066 Epalinges Switzerland

The search for a thrombopoietic agent has resulted in the identification of numerous cytokines and growth factors with thrombopoietic activity. However, with the exception of interleukin (IL)-11 and thrombopoietin (TPO), the megakaryopoietic activity of most of these molecules has not produced clearly identifiable clinical benefits. Despite the relatively modest effect of IL-11 on megakaryocyte and platelet production in vitro and in vivo, it does reduce the need for platelet transfusions in specialized clinical settings. In contrast, the c-Mpl ligand TPO has been shown to be a potent stimulator of megakaryocyte and platelet production both in vitro and in vivo. Clinical studies are being conducted with two different preparations of the c-Mpl ligand: recombinant human thrombopoietin (rhTPO) and pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF). A recombinant form of the complete human molecule, rhTPO is glycosylated and produced in mammalian cells. PEG-rHuMGDF consists of only the receptor-binding domain linked to a polyethylene glycol (PEG) moiety and is generated in Escherichia coli. Although c-Mpl ligands are still being evaluated, preliminary evidence indicates that these molecules can elevate platelet counts and may be useful in a range of clinical contexts. This report discusses aspects of the biology behind the clinical actions of IL-11 and the c-Mpl ligands.

关键词：血小板/细胞学血小板/药物作用细胞因子类/血液细胞因子类/药理学细胞因子类/生理学生长物质/血液生长物质/药理学生长物质/生理学血细胞生成/药物作用白细胞介素11/血液白细胞介素11/药理学白细胞介素11/生理学巨核细胞/细胞学巨核细胞/药物作用血小板生成素/血液血小板生成素/药理学血小板生成素/生理学动物人类

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Expression of the collagen receptor glycoprotein VI during megakaryocyte differentiation

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BLOOD 2000年第8期96卷 2740-2745页

作者： Berlanga, O Bobe, R Becker, M Murphy, G Leduc, M Bon, C Barry, FA Gibbins, JM Garcia, P Frampton, J Watson, SP Univ Oxford Dept Pharmacol Oxford OX1 3QT England John Radcliffe Hosp Inst Mol Med Oxford OX3 9DU England Inst Pasteur Unite Venins Paris France Univ Reading Sch Anim & Microbial Sci Reading RG6 2AJ Berks England

This study examined the expression of the platelet collagen receptor glycoprotein VI (GPVI) in megakaryocyte cell lines and primary megakaryocytes by reverse transcriptase-polymerase chain reaction and by flow cytometry and ligand blotting using the snake venom toxin convulxin. Expression of GPVI is increased in the megakaryoblastic cell lines HEL and CMK on differentiation with the phorbol ester phorbol 12-myristate Il-acetate (PMA), along with the Fe receptor gamma -chain (FcR gamma -chain). The increase in GPVI expression is associated with marked potentiation of tyrosine phosphorylation and Ca++ elevation in response to convulxin. Syk, linker for activated T cells, and phospholipase C gamma2 (PLC gamma2) are among the proteins tyrosine phosphorylated on convulxin stimulation in PMA-differentiated HEL cells. Studies on primary murine megakaryocytes grown in vitro confirmed that GPVI is up-regulated in parallel with functional activation, assessed by measurement of [Ca++](i), during differentiation. The results demonstrate that expression of GPVI is upregulated along with the FcR gamma -chain during differentiation of megakaryocytes, (C) 2000 by The American Society of Hematology.

关键词：血小板/代谢钙信号/药物作用细胞分化/药物作用细胞系/药物作用细胞系/代谢响尾蛇毒液类/药理学流式细胞术基因表达调控发育期/药物作用外源凝集素类 C型巨核细胞/细胞学巨核细胞/药物作用巨核细胞/代谢血小板膜糖蛋白类/生物合成血小板膜糖蛋白类/遗传学 RNA 信使/生物合成 RNA 信使/遗传学受体 IgG/生物合成受体 IgG/遗传学逆转录聚合酶链反应十四酰佛波乙酯/药理学肿瘤细胞培养的/药物作用增量调节/药物作用动物人类小鼠

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Role of the distal half of the c-Mpl intracellular domain in control of platelet production by thrombopoietin in vivo

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MOLECULAR AND CELLULAR BIOLOGY 2000年第2期20卷 507-515页

作者： Luoh, SM Stefanich, E Solar, G Steinmetz, H Lipari, T Pestina, TI Jackson, CW de Sauvage, FJ Genentech Inc Dept Mol Oncol San Francisco CA 94080 USA Genentech Inc Dept Cardiovasc San Francisco CA 94080 USA Genentech Inc Dept Metab & Pharmacokinet San Francisco CA 94080 USA St Jude Childrens Res Hosp Div Expt Hematol Memphis TN 38105 USA

The cytokine thrombopoietin (TPO) controls the formation of megakaryocytes and platelets from hematopoietic stem cells. TPO exerts its effect through activation of the c-Mp1 receptor and of multiple downstream signal transduction pathways. While the membrane-proximal half of the cytoplasmic domain appears to be required for the activation of signaling molecules that drive proliferation, the distal half and activation of the mitogen-activated protein kinase pathway have been implicated in mediating megakaryocyte maturation in vitro. To investigate the contribution of these two regions of c-Mp1 and the signaling pathways they direct in mediating the function of TPO in vivo, we used a knock-in (KI) approach to delete the carboxy-terminal 60 amino acids of the c-Mp1 receptor intracellular domain. Mice lacking the C-terminal 60 amino acids of c-Mp1 (Delta 60 mice) have normal platelet and megakaryocyte counts compared to wild-type mice. Furthermore, platelets in the KI mice are functionally normal, indicating that activation of signaling pathways connected to the C-terminal half of the receptor is not required for megakaryocyte differentiation or platelet production. However, Delta 60 mice have an impaired response to exogenous TPO stimulation and display slower recovery from myelosuppressive treatment, suggesting that combinatorial signaling by both ends of the receptor intracellular domain is necessary for an appropriate acute response to TPO.

关键词：血细胞计数血小板/细胞学血小板/药物作用血小板/生理学细胞分化/药物作用细胞分裂/药物作用细胞培养的外显子/遗传学纤维蛋白原/代谢血细胞生成造血干细胞/细胞学造血干细胞/药物作用巨核细胞/细胞学巨核细胞/药物作用小鼠转基因肿瘤蛋白质类磷酰化/药物作用磷酸酪氨酸/代谢血小板活化倍性原癌基因蛋白质类/化学原癌基因蛋白质类/遗传学原癌基因蛋白质类/代谢受体细胞因子/化学受体细胞因子/遗传学受体细胞因子/代谢受体血小板生成素序列缺失/遗传学信号传导/药物作用血小板生成素/药理学时间因素动物小鼠

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A model for studying megakaryocyte development and biology

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PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 1999年第6期96卷 3065-3070页

作者： Murphy, GJ Leavitt, AD Univ Calif San Francisco Dept Lab Med San Francisco CA 94143 USA Univ Calif San Francisco Dept Internal Med San Francisco CA 94143 USA

The limited current understanding of megakaryocyte-lineage development and megakaryocyte biology is in large part because of a paucity of useful systems in which to conduct experiments. To overcome this problem, we have developed a transgenic mouse that uses the GP-Ib alpha: regulatory sequences to achieve megakaryocyte-lineage restricted expression of an avian retroviral receptor. Through the transgenic avian receptor, avian retroviruses can efficiently and selectively infect megakaryocyte-lineage cells in. vitro and in vivo. Serial infections can be performed to introduce and express multiple genes in the same cell. We have used this system to generate and characterize a pure population of primary CD41-positive megakaryocyte progenitors.

关键词：细胞分化/遗传学细胞系细胞谱系/遗传学鸡巨核细胞/细胞学小鼠转基因血小板糖蛋白GPⅡb-Ⅲa复合物血小板糖蛋白GPⅠb-Ⅸ复合物/遗传学动物小鼠

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The residual megakaryocyte and platelet production in c-Mpl-deficient mice is not dependent on the actions of interleukin-6, interleukin-11, or leukemia inhibitory factor

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BLOOD 2000年第2期95卷 528-534页

作者： Gainsford, T Nandurkar, H Metcalf, D Robb, L Begley, CG Alexander, WS Walter & Eliza Hall Inst Med Res Melbourne Vic 3050 Australia Royal Melbourne Hosp Cooperat Res Ctr Cellular Growth Factors Melbourne Vic Australia Royal Melbourne Hosp Rotary Bone Marrow Res Labs Melbourne Vic Australia

Mice lacking thrombopoietin (TPO) or its receptor c-Mpl are severely thrombocytopenic, consistent with a dominant physiological role for this cytokine in megakaryocytopoiesis, However, these mice remain healthy and show no signs of spontaneous hemorrhage, implying that TPO-independent mechanisms for platelet production exist and are sufficient for hemostasis. To investigate the roles of cytokines that act through the gp130 signaling chain in the residual platelet production of mpl(-/-) mice, mpl -/-IL-6(-/-), mpl(-/-)LIF(-/-), and mpl(-/-)IL-11R alpha(-/-) double-mutant mice were generated. In each of these compound mutants, the number of circulating platelets was no lower than that observed in mice lacking only the c-mpl gene. Moreover, the deficits in the numbers of megakaryocytes and megakaryocyte progenitor cells in the bone marrow and spleen were no further exacerbated in mpl(-/-)L-6(-/-), mpl(-/-)LIF(-/-), or mpl(-/-) IL-11R alpha(-/-) double-mutant mice compared, with those in Mpl-deficient animals. In single IL-6(-/-), LIF-/-, and IL-11R alpha(-/-) mutant mice, platelet production was normal. These data establish that, as single regulators, IL-6, IL-11, and LIF have no essential role in normal steady-state megakaryocytopoiesis, and are not required for the residual megakaryocyte and platelet production seen in the c-mpl(-/-) mouse. (Blood, 2000;95:528-534) (C) 2000 by The American Society of Hematology.

关键词：血小板/细胞学骨髓细胞/细胞学基因型生长抑制物/缺乏生长抑制物/遗传学生长抑制物/生理学血细胞生成/遗传学血细胞生成/生理学造血干细胞/细胞学造血干细胞/药物作用造血干细胞/生理学白细胞介素11/缺乏白细胞介素11/遗传学白细胞介素11/生理学白细胞介素6/缺乏白细胞介素6/遗传学白细胞介素6/生理学白血病抑制因子淋巴因子/缺乏淋巴因子/遗传学淋巴因子/生理学巨核细胞/细胞学小鼠基因敲除肿瘤蛋白质类血小板计数原癌基因蛋白质类/缺乏原癌基因蛋白质类/遗传学原癌基因蛋白质类/生理学受体细胞因子受体血小板生成素脾/细胞学血小板生成素/缺乏血小板生成素/遗传学血小板生成素/生理学动物小鼠

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Radiation sensitivity of megakaryocyte colony-forming cells in human placental and umbilical cord blood

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RADIATION RESEARCH 2000年第2期153卷 144-152页

作者： Kashiwakura, I Kuwabara, M Inanami, O Murakami, M Hayase, Y Takahashi, TA Takagi, Y Hokkaido Coll Pharm Lab Radippharmaceut Sci Otaru Hokkaido 0470264 Japan Hokkaido Univ Dept Environm Vet Sci Grad Sch Vet Med Sapporo Hokkaido 0600818 Japan Univ Tokyo Inst Med Sci Cell Proc Dept Minato Ku Tokyo 1080071 Japan

The in vitro radiation sensitivity of CPU-Meg isolated from human placental and umbilical cord blood was evaluated in plasma clot cultures stimulated by recombinant human cytokines, including thrombopoietin, the FLT3 ligand (FLT3LG), interleukin-3, interleukin-11 and stem cell factor. The CD34(+) cells were irradiated with X rays at a dose rate of 73 cGy/min, The megakaryocyte colonies were identified by using an FITC-conjugated antibody to glycoprotein IIbIIIa and were classified into two groups based on colony size: large colonies (immature CPU-Meg) and small colonies (mature CPU-Meg), Treatment with thrombopoietin alone or in combination with FLT3LG and/or interleukin-11 gave exponential radiation survival curves (D-0 for immature CFU-Meg = 56-77 cGy, D-0 for mature CPU-Meg = 86 cGy-1.12 Gy), while marked shoulders were observed on the survival curves for colonies supported by the combination of thrombopoietin, interleukin-3 and stem cell factor (D-0 for immature CFU-Meg = 89-98 cGy;D-0 for mature CFU-Meg = 1.25-1.31 Gy). Our results showed that the immature CPU-Meg were more radiosensitive than the mature CPU-Meg and that the combination of cytokines, including thrombopoietin, interleukin-3 and stem cell factor, affected the radiation sensitivity of CFU-Meg to the same extent as with thrombopoietin alone or in combination with FLT3LG and/or interleukin-11. (C) 2000 by Radiation Research Society.

关键词：抗原 CD34/代谢细胞分裂/药物作用细胞存活/辐射效应细胞因子类/药理学胎血/细胞学巨核细胞/细胞学巨核细胞/免疫学巨核细胞/辐射效应胎盘/细胞学辐射耐受性重组蛋白质类/药理学血小板生成素/药理学人类

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