c-KIT expression enhances the leukemogenic potential of 32D cells.

Hu, Qinglong; Trevisan, Maryanne; Xu, Yi; Dong, Weifeng; Berger, Stuart A.; Lyman, Stewart D.; Minden, Mark D.

doi:10.1172/jci117954

Cited by 20 publications

(7 citation statements)

References 49 publications

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“…The leukemogenic potential of SCF driven c-KIT activation could be demonstrated by transfection of c-KIT into 32D cells with subsequent injection into syngeneic hosts. In contrast to animals injected with control 32D cells, these animals died of overwhelming leukemia [109]. Besides activation through SCF, c-KIT can also be mutationally activated.…”

Section: Genetic Abnormalities In Upstream Receptorsmentioning

confidence: 91%

Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Zebisch¹,

Czernilofsky²,

Kéri³

et al. 2007

CMC

104

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Aberrant signaling caused by mutations in the RAS-RAF-MEK-ERK pathway and its upstream activators critically contributes to human tumor development. Strategies, which aim at inhibiting hyperactive signaling molecules, appear conceptually straight forward, but their translation into clinical practice has been hampered by many setbacks. Understanding structure, function and regulation of this intracellular pathway as well as its crosstalk with other signaling activities in the cell will be essential to ensure reasonable usage of new therapeutic possibilities. This review provides an understanding of this signaling cascade as revealed by genetic and biochemical approaches and discusses the existing or arising possibilities to interfere with unphysiological activation in cancer. Signaling aberrations and signal transduction therapies will be discussed exemplary for two types of hematological neoplasia, acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). In the future understanding the role of tumor stem cells, both as a source of tumor recurrence and tumor heterogeneity, the signals controlling their fate as well as epigenetic changes in cancer will be the next critical steps to further advance the applicability of these novel therapeutic strategies.

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Section: Genetic Abnormalities In Upstream Receptorsmentioning

confidence: 91%

Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Zebisch¹,

Czernilofsky²,

Kéri³

et al. 2007

CMC

104

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show abstract

“…The constitutive activation of this essential signaling pathway might contribute to BZ's ability to induce acute myeloid leukemia. In support of this speculation, it has been reported that constitutive overexpression of the c-kit receptor in 32D myeloblasts results in a population of cells that when injected into the bone marrow of syngeneic mice results in acute leukemia in four to six weeks [51]. Experiments to test the leukemogenic capacity of HQ-treated, incompletely differentiated 32D myeloblasts in syngeneic mice are in progress.…”

Section: Il-3 Alonementioning

confidence: 92%

Hydroquinone, a Bioreactive Metabolite of Benzene, Inhibits Apoptosis in Myeloblasts

1996

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Abstract. Hydroquinone (a major marrow metabolite of the leukemogen, benzene) induces incomplete granulocytic differentiation of mouse myeloblasts to the myelocyte stage, and also causes an increase in the number of myelocytes. This was confirmed using the normal interleukin 3 (IL-3)-dependent mouse myeloblastic 32D cell line. The hydroquinoneinduced twofold increase in the number of IL-3-treated myelocytes does not result from stimulation of IL-3-induced proliferation. Hydroquinone's ability to effect this increase through an inhibition of apoptosis was investigated using mouse 32D and human HL-60 myeloblasts. Apoptosis induced by staurosporine treatment (0.5-1.0 µM) of HL-60 cells (50%) and 32D cells (15%) or by IL-3 withdrawal from 32D myeloblasts was determined by monitoring the development of characteristic morphological features and confirmed by the appearance of a typical nucleosomal DNA ladder upon agarose gel electrophoresis. Concentration of hydroquinone (1-6 µM) that induce differentiation in 32D myeloblasts caused a concentration-dependent inhibition of staurosporine-induced apoptosis in both cell lines, with a 50% inhibitory concentration of 3 µM, and prevented apoptosis in IL-3-deprived 32D cells. Hydroquinone inhibition of apoptosis in myeloblasts, like hydroquinone-induced granulocytic differentiation, required myeloperoxidase-mediated oxidation of hydroquinone to its reactive species, p-benzoquinone, and was inhibited 50% by the peroxidase inhibitor, indomethacin (20 µM). p-benzoquinone (3 µM) was shown to cause a 50% inhibition of CPP32, an IL-1β converting enzyme/Ced-3 cysteine protease involved in the implementation of apoptosis and present in myeloid cells. The ability of hydroquinone to induce a program of differentiation in the myeloblast that proceeds only to the myelocyte stage coupled with its ability to inhibit the CPP32 protease and, thereby, apoptosis of the proliferating myelocytes, may have important implications for benzene-induced acute myeloid leukemia.

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“…These were collected, concentrated, and checked for purity by silver stain. SLF was also conjugated with biotin (Sigma) as described (30).…”

Section: Methodsmentioning

confidence: 99%

Phosphatidylinositol 3-Kinase and Ca2+ Influx Dependence for Ligand-stimulated Internalization of the c-Kit Receptor

Gommerman

Rottapel

Berger

1997

Journal of Biological Chemistry

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c-Kit is a receptor tyrosine kinase and a member of the subfamily that includes the PDGF, 1 CSF-1, and flt-3/flk-2 receptors. Together with its ligand steel factor (SLF), c-Kit is a key controlling receptor for a number of cell types including hematopoietic stem cells, mast cells, melanocytes, and germ cells. c-Kit is the gene product of the W locus in mice (1), and its ligand SLF is the product of the sl locus (2, 3). Mutations in either locus severely affect the growth and survival of stem cells of these tissues.As with other receptor tyrosine kinases, stimulation of the c-Kit receptor with SLF results in the recruitment and tyrosine phosphorylation of SH2-containing second messenger-generating enzymes (4) such as phospholipase C-␥ and PI3-kinase (5, 6). The phosphorylated lipid products of these enzymes stimulate a variety of intracellular processes including Ca 2ϩ mobilization and actin reorganization (7-9). Coincident with second messenger generation, the process of receptor internalization is also initiated. Within minutes following ligand binding, receptors cluster in dimers or oligomers and internalize by endocytosis, likely through clathrin-coated pits (10 -12). Eventually, clathrin coats are removed, and the remaining vesicles fuse with endosomes, late endosomes, and ultimately lysosomes, resulting in receptor degradation.Numerous deletion and mutagenesis studies have been carried out to map regions of receptor tyrosine kinases required for ligand-stimulated internalization (13-22). Tyrosine kinase activity (23, 24), autophosphorylation sites (17, 18), and interactions with second messenger-generating enzymes have been implicated. In particular, recruitment and activation of PI3-kinase have been associated with ligand-stimulated internalization of the PDGF receptor (14). Receptors carrying mutations within the cytoplasmic domain that disrupt the PI3-kinase-binding site are impaired in the later stages of endocytosis (25). However, conflicting results with a deletion mutant encompassing this binding site demonstrate no impairment in any stage of endocytosis (16).Ligand-stimulated endocytosis of c-Kit was investigated by Yee et al. (26). They reported that a c-Kit mutant with no kinase activity was impaired for ligand-stimulated internalization. Individual mutations converting tyrosines 719 and 821 to phenylalanines, however, failed to affect internalization, although Phe-821 was impaired for mitogenesis (27). Tyr-719 is located in the kinase insert region of the c-Kit catalytic domain. In its phosphorylated form, it forms part of a consensus binding site for the p85 subunit of PI3-kinase and has been shown to mediate this interaction in vitro and in vivo (6).We have also examined the role of PI3-kinase activation on ligand-stimulated internalization of c-Kit. We found that in the absence of PI3-kinase activation, the c-Kit receptor internalizes but remains localized near the inner aspect of the plasma membrane. However, when both PI3-kinase and Ca 2ϩ influx are inhibited, clathrin fails to co-immunoprec...

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c-KIT expression enhances the leukemogenic potential of 32D cells.

Abstract: The growth of human leukemic cells in culture and in vivo is dependent upon

Cited by 20 publications

References 49 publications

Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Signaling Through RAS-RAF-MEK-ERK: from Basics to Bedside

Hydroquinone, a Bioreactive Metabolite of Benzene, Inhibits Apoptosis in Myeloblasts

Phosphatidylinositol 3-Kinase and Ca2+ Influx Dependence for Ligand-stimulated Internalization of the c-Kit Receptor

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