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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene expression of various cytokine receptors in CD7+ acute lymphoblastic leukemia (ALL) cells in relation to responsiveness to these cytokines was examined by reverse transcription polymerase chain reaction and Northern blot studies. Leukemic cells from all of seven CD7+ ALL patients examined fulfilled the criteria for ALL according to the FAB classification; surface CD3 was absent in all of these patients, while cytoplasmic CD3 and/or CD3 epsilon mRNA were found in all of them. Samples from six of the seven patients at initial disease expressed the granulocyte colony-stimulating factor receptor (G-CSFR) gene. Leukemic cells with G-CSFR transcripts from one patient at initial disease showed growth response to G-CSF in vitro, and those from two other patients became responsive to G-CSF at relapse. Neither in vitro nor in vivo myeloid differentiation was observed in any samples that responded to G-CSF. Interleukin 3R alpha (IL-3R alpha) gene was expressed in samples from one patient at initial disease and from two patients at relapse. GM-CSFR beta gene mRNA was detected in two patients with IL-3R alpha mRNA. Our results show that the leukemic cells in these CD7+ ALL patients frequently expressed G-CSFR as a functional property, thus calling attention to the appropriate clinical application of G-CSF for ALL patients.
Leukemia 1993 Aug
PMID:Frequent gene expression of granulocyte colony-stimulating factor (G-CSF) receptor in CD7+ surface CD3- acute lymphoblastic leukaemia. 768 38

The granulocyte colony-stimulating factor receptor (G-CSFR) was overexpressed in WEHI-3B D+ myelomonocytic leukemia cells by the transfection of an expression plasmid containing the murine G-CSFR cDNA. Two different forms of the G-CSFR were observed in these cells by western blotting. Metabolic labeling and cell surface labeling demonstrated that the majority of the G-CSFR exists in a non-mature form and is presumably present in the cytoplasm as a 115-kDa protein. A relatively small portion of the G-CSFR is present as the fully mature form on the cell surface as a 150-kDa protein; this form of the G-CSFR binds to granulocyte colony-stimulating factor (G-CSF). Both the mature and non-mature forms of the G-CSFR appear to be N-glycosylated, as determined by glycanase digestion and inhibition of glycosylation by tunicamycin. Glycosylation of the G-CSFR may be of importance for the transport of the receptor to the cell surface.
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PMID:Evidence for the glycosylation of the granulocyte colony-stimulating factor receptor. 799 29

Interleukin-7 (IL-7) stimulates the proliferation of normal and leukemic B and T cell precursors and T lymphocytes. Activation of the JAK/STAT pathway has been implicated in IL-7R signaling. We investigated which STAT complexes are formed upon stimulation of B cell precursor acute lymphoblastic leukemia (BCP-ALL) cells with IL-7. Gel retardation assays with STAT-binding oligonucleotides showed that IL-7 induces the formation of two major STAT complexes in BCP-ALL cells. Supershifts with anti-STAT antibodies identified these as STAT1 and STAT5 complexes. This pattern of STAT activation was seen in all BCP-ALL cases that respond to IL-7 in proliferation assays. IL-7 also induced STAT/DNA binding in BCP-ALL cases that failed to proliferate in response to IL-7, suggesting that the ability of IL-7R to activate the JAK/STAT pathway per se is not sufficient for proliferation induction. To determine the contribution of the cytoplasmic domain of the IL-7 receptor alpha chain (IL-7R alpha) to activation of STAT proteins, transfectants of the murine pro-B cell line BAF3 were made that express chimeric receptors consisting of the extracellular domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) and the transmembrane and intracellular domains of human IL-7R alpha. Activation of the chimeric G-CSF-R/IL-7R alpha with G-CSF resulted in a full proliferative response and induced the phosphorylation of JAK1 but not JAK2. Major STAT complexes activated by G-CSF-R/IL-7R alpha contained STAT1 or STAT5, while some formation of STAT3-containing complexes was also seen. These findings establish that STAT1 and STAT5, and possibly STAT3, are activated upon stimulation of precursor B cells with IL-7. The data further indicate that the IL-7R alpha chains are directly involved in the activation of JAKs and STATs and have a major role in proliferative signaling in precursor B cells.
Leukemia 1996 Aug
PMID:Interleukin-7 signaling in human B cell precursor acute lymphoblastic leukemia cells and murine BAF3 cells involves activation of STAT1 and STAT5 mediated via the interleukin-7 receptor alpha chain. 870 37

Previously, nonsense mutations in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R) have been described in three patients with severe congenital neutropenia (SCN) (Proc Natl Acad Sci USA 1994; 91: 4480; New Engl J Med 1995; 333: 487). The mutations resulted in the truncation of the carboxy-terminal region of G-CSF-R essential for transduction of maturation signals. Two of these patients developed acute myeloblastic leukemia (AML). We present the results of a search among 20 additional cases of congenital neutropenia (CN) and SCN for the presence of mutations in the cytoplasmic domain of G-CSF-R. This series includes patients with familial and nonfamilial forms of CN and SCN. Mutations in the G-CSF-R gene were found in two new SCN cases. These mutations were nonsense mutations, located in the same cytoplasmic region of G-CSF-R as those found earlier, resulting in the truncation of the C-terminus. Both of these patients developed AML. None of the other patients showed clinical symptoms or cytogenetic features indicative of AML or progression to leukemia. The analysis in this extended series of patients thus has revealed five SCN cases with G-CSF-R mutations, four of whom developed AML. These results add support to the notion that mutations in the G-CSF-R gene, affecting the maturation signaling function of the receptor, define a distinct subgroup of SCN with increased susceptibilty to AML.
Leukemia 1997 Jan
PMID:Mutations in the granulocyte colony-stimulating factor receptor gene in patients with severe congenital neutropenia. 900 27

It is likely that leukemia results, at least in part, from mutations that lead to a block in the normal process of differentiation. A defined region of the cytoplasmic domain of the granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for maturation or differentiation of myeloid progenitor cells. Mutations in this region have been found in some patients with severe congenital neutropenia (SCN) who subsequently evolved to acute myeloid leukemia (AML). To determine if mutations of the G-CSF-R are more widespread in hematological malignancies, we have investigated a total of 47 patients, including 29 patients with blast crisis of chronic myeloid leukemia (CML-BC) and 18 patients with de novo acute leukemia as well as 19 normal controls, by RT-PCR and SSCP analysis. Two point mutations were found in a single individual with secondary AML (FAB type M1). The first was heterozygous and is predicted to replace the normal glutamine at position 718 with a stop codon, leading to a truncated protein. An identical mutation has been described previously and shown to act in a dominant negative manner. The second mutation was homozygous and would substitute a lysine for the normal glutamic acid at position 785. No mutations were found in any other patient or control samples. We conclude that mutations in the cytoplasmic domain of the G-CSF-R are infrequent in CML-BC or acute leukemia but may contribute to malignant transformation in some cases.
Leukemia 1997 Jul
PMID:Rarity of dominant-negative mutations of the G-CSF receptor in patients with blast crisis of chronic myeloid leukemia or de novo acute leukemia. 920 82

The membrane-proximal cytoplasmic region of the granulocyte colony-stimulating factor receptor (G-CSFR) is known to be essential for the proliferation signal, with a more distal region being required for the differentiation signal. Such a separation of functional domains raises the possibility that mutations occurring at these regions may contribute to cell proliferation in the absence of differentiation, this being the most important characteristic in acute leukemia cells. Therefore, we analysed the structural abnormalities at the transmembrane and cytoplasmic region of G-CSFR in a significant number of patients with various myeloid malignancies. When we examined the genomic DNA of G-CSFR obtained from 41 patients with acute myelogenous leukemia (AML), 18 with chronic myelogenous leukemia (CML), 7 with myelodysplastic syndrome (MDS), 2 with chronic myelomonocytic leukemia and 1 with chronic neutrophilic leukemia, we found a polymorphism in 3 patients, but no significant pathogenic mutations in any patients. The screening for this polymorphism in 100 hematologically normal controls revealed that it may be useful as a linkage marker for population and family studies, because the heterozygosity index is at a high level (0.055). While there have been several reports discussing the leukemogenic potential of mutations in the cytokine/hematopoietin receptor superfamily, genetic alterations in the transmembrane and cytoplasmic region of G-CSFR do not seem to play a pathogenic role in leukemia.
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PMID:Analysis of the granulocyte colony-stimulating factor receptor gene structure using PCR-SSCP in myeloid leukemia and myelodysplastic syndrome. 954 19

Approximately 25-30% of childhood pre-B cell acute lymphoblastic leukemias (pre-B ALL) is characterized by the presence of a (1;19)(q23;p13.3) translocation. The presence of this translocation is generally accompanied by a poor prognosis. The chimeric gene resulting from this chromosomal rearrangement encodes a hybrid transcription factor, E2A-Pbx1. In an attempt to delineate the genetic cascade initiated by E2A-Pbx1, we sought to identify genes that are deregulated by this transcription factor in t(1;19) pre-B ALL. We show here that the gene encoding the granulocyte colony-stimulating factor receptor (G-CSFr) is specifically upregulated in pre-B cells expressing E2A-Pbx1. G-CSFr is also expressed in cell lines established from t(1;19) pre-B cell leukemia and on primary t(1;19) tumor cells, but not on control cells. These data indicate that G-CSFr gene is a target for deregulation by E2A-Pbx1.
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PMID:The gene encoding the granulocyte colony-stimulating factor receptor is a target for deregulation in pre-B ALL by the t(1;19)-specific oncoprotein E2A-Pbx1. 969 44

In approximately 20% of cases of severe congenital neutropenia (SCN), mutations are found in the gene encoding the granulocyte colony-stimulating factor receptor (G-CSF-R). These mutations introduce premature stop codons, which result in truncation of 82-98 COOH-terminal amino acids of the receptor. SCN patients who develop secondary myelodysplastic syndrome and acute myeloid leukemia almost invariably acquired a GCSFR mutation, suggesting that this genetic alteration represents a key step in leukemogenesis. Here we show that an equivalent mutation targeted in mice (gcsfr-Delta715) results in the selective expansion of the G-CSF- responsive progenitor (G-CFC) compartment in the bone marrow. In addition, in vivo treatment of gcsfr-Delta715 mice with G-CSF results in increased production of neutrophils leading to a sustained neutrophilia. This hyperproliferative response to G-CSF is accompanied by prolonged activation of signal transducer and activator of transcription (STAT) complexes and extended cell surface expression of mutant receptors due to defective internalization. In view of the continuous G-CSF treatment of SCN patients, these data provide insight into why progenitor cells expressing truncated receptors clonally expand in vivo, and why these cells may be targets for additional genetic events leading to leukemia.
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PMID:Sustained receptor activation and hyperproliferation in response to granulocyte colony-stimulating factor (G-CSF) in mice with a severe congenital neutropenia/acute myeloid leukemia-derived mutation in the G-CSF receptor gene. 998 83

Granulocyte colony-stimulating factor receptor (G-CSFR) regulates the proliferation and differentiation of neutrophilic progenitor cells through interaction with its cytokine. Exposure of WEHI-3B D+ myelomonocytic leukemia and myeloid LGM-1 cells overexpressing the G-CSFR to G-CSF resulted in induction of differentiation as measured by (1) the ability to reduce nitroblue tetrazolium (NBT), (2) the expression of Mac-I antigen, and (3) the expression of FcgammaII/III receptor. Mutational analyses indicated that distinct regions of the cytoplasmic domain were critical for efficient induction of each functional marker. The membrane proximal region containing homology sequences of boxes 1 and 2 was important for the activation of all three functional markers of mature neutrophils. Induction of the capacities to express Mac-I antigen or FcgammaII/III receptor also required additional sequences in the membrane proximal region between amino acids 70 and 100 and may be dependent on the phosphorylation of Tyr703. The findings suggest that distinct sequences within the amino-terminal region of the cytoplasmic domain of the receptor are sufficient to induce these functional markers of differentiation, and receptor tyrosine phosphorylation may be necessary.
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PMID:Functional differentiation signals mediated by distinct regions of the cytoplasmic domain of the granulocyte colony-stimulating factor receptor. 1033 83

We report the cellular characteristics of cells from three patients with de novo acute myelocytic leukaemia (AML) with t(16;21)(p11;q22), two M4 and one M5a according to the FAB classification, and two permanent cell lines with t(16;21)(p11;q22), TSU1621MT and YNH-1. The FUS/ERG fusion mRNA was demonstrated in all cases by reverse transcriptase-polymerase chain reaction (RT-PCR). The immunophenotypes of the AML cells, and YNH-1 and TSU1621MT cell lines with t(16;21) were characterized as CD34+CD33+CD13+CD11b+CD18+CD56+ HLA-DR-/+. Cells from all samples strongly expressed c-kit, granulocyte colony-stimulating factor receptor (G-CSFR), c-fms (macrophage colony-stimulating factor receptor), interleukin-3 receptor alpha chain (IL-3Ralpha), and granulocyte macrophage colony-stimulating factor receptor alpha chain (GM-CSFRalpha), and these data corresponded well to the growth responsiveness to the cytokines. IL-2Ralpha expression was also found in all t(16;21) samples, but IL-2 did not act on the proliferation of the leukaemic cells in in vitro cultures. G-CSF distinctly promoted the proliferation of leukaemic cells of t(16;21) AML, but did not enhance the expression of MPO and neutrophil differentiation of these cells. Our findings indicate that AML cells with t(16;21) preserve stem cell properties such as CD34 and c-kit expression, and suggest that they have the potential to differentiate into a monocytic lineage. The relationship between the unique cellular characteristics (especially CD56 and IL-2Ralpha expression) and FUS/ERG protein remains undetermined.
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PMID:Myeloid differentiation antigen and cytokine receptor expression on acute myelocytic leukaemia cells with t(16;21)(p11;q22): frequent expression of CD56 and interleukin-2 receptor alpha chain. 1035 36


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