Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte colony-stimulating factor (G-CSF) receptors on the gated leukemic blast cells from newly diagnosed patients with acute leukemia or crisis of chronic myelogenous leukemia were investigated using flow cytometric detection. Surface marker analysis and cytochemical studies were conducted simultaneously to characterize the blast cells. Among 24 leukemia cases examined, G-CSF receptor-positive blast cells were detected in all 11 cases of acute myeloblastic leukemia even though the percentage range of positive cells was widely variable. On the other hand, they were not detected on the blast cells from patients with peroxidase-negative acute lymphoblastic leukemia with no myeloid surface antigens. However, G-CSF receptors were demonstrated in significant amounts on blast cells from 5 of 8 cases of peroxidase-negative acute leukemia expressing both myeloid and lymphoid surface antigens (biphenotypic leukemia). The percentage of blast cells positive for G-CSF receptors was significantly smaller in biphenotypic cases [33 +/- 14% (SD)] than in acute myeloblastic leukemia cases [65 +/- 22%] (P less than 0.01). The percentage expression of CD13 antigen by blast cells was significantly related to their percentage positivity for G-CSF receptors (rs = 0.50, P less than 0.05). These findings indicate that the distribution of flow cytometrically detectable G-CSF receptors on leukemic cells possessing myeloid characteristics may be related to the maturation process.
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PMID:Granulocyte colony-stimulating factor receptors on human acute leukemia: biphenotypic leukemic cells possess granulocyte colony-stimulating factor receptors. 153 71

Two patients with chronic myelocytic leukemia (CML) mixed crisis and one with Philadelphia-chromosome-positive (Ph1 +) acute lymphoblastic leukemia (ALL) with cross-lineage nature had a considerable number of granulocytes with monoclonally rearranged immunogenotype. The gene configurations of immunoglobulin heavy chain (IgH), T-cell receptor beta chain (TCR beta), and gamma chain (TCR gamma) in the granulocytic cells were identical to those in the blasts, indicating that both the blasts and the granulocytes were derived from common leukemic progenitors with the IgH gene rearrangements. In a colony assay of cells from in the Ph1 + ALL patient, the leukemic cells showed the potential to differentiate into granulocytes in the presence of either granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte-CSF (G-CSF). Interleukin 7 (IL-7) exerted synergistic effects on colony and cluster formation in cultures with these cytokines. Further, IL-3, GM-CSF, and G-CSF receptor gene expression was found in the leukemic cells. Our findings indicate that the Ph1 + common progenitors in these three patients preserved the potential for granulocytic differentiation even after the occurrence of the Ig (and TCR) gene rearrangements as the first genomic event in lymphocyte differentiation. The phenomenon of cross-lineage in leukemic cells, at least in Ph1 + leukemia, can be considered to demonstrate the potential of leukemic progenitors to differentiate in multiple directions.
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PMID:A granulocytic population with rearranged immunogenotype in chronic myelocytic leukemia blast crisis and Philadelphia-chromosome-positive acute leukemia with cross-lineage nature. 838 Nov 95

All-trans retinoic acid (ATRA) is successfully used in the cyto-differentiating treatment of acute promyelocytic leukemia (APL). Paradoxically, APL cells express PML-RAR, an aberrant form of the retinoic acid receptor type alpha (RAR alpha) derived from the leukemia-specific t(15;17) chromosomal translocation. We show here that AM580, a stable retinobenzoic derivative originally synthesized as a RAR alpha agonist, is a powerful inducer of granulocytic maturation in NB4, an APL-derived cell line, and in freshly isolated APL blasts. After treatment of APL cells with AM580 either alone or in combination with granulocyte colony-stimulating factor (G-CSF), the compound induces granulocytic maturation, as assessed by determination of the levels of leukocyte alkaline phosphatase, CD11b, CD33, and G-CSF receptor mRNA, at concentrations that are 10- to 100-fold lower than those of ATRA necessary to produce similar effects. By contrast, AM580 is not effective as ATRA in modulating the expression of these differentiation markers in the HL-60 cell line and in freshly isolated granulocytes obtained from the peripheral blood of chronic myelogenous leukemia patients during the stable phase of the disease. In NB4 cells, two other synthetic nonselective RAR ligands are capable of inducing LAP as much as AM580, whereas RAR beta- or RAR gamma-specific ligands are totally ineffective. These results show that AM580 is more powerful than ATRA in modulating the expression of differentiation antigens only in cells in which PML-RAR is present. Binding experiments, using COS-7 cells transiently transfected with PML-RAR and the normal RAR alpha, show that AM580 has a lower affinity than ATRA for both receptors. However, in the presence of PML-RAR, the synthetic retinoid is a much better transactivator of retinoic acid-responsive element-containing promoters than the natural retinoid, whereas, in the presence of RAR alpha, AM580 and ATRA have similar activity. This may explain the strong cyto-differentiating potential of AM580 in PML-RAR-containing leukemic cells.
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PMID:AM580, a stable benzoic derivative of retinoic acid, has powerful and selective cyto-differentiating effects on acute promyelocytic leukemia cells. 860 43

Granulocyte colony-stimulating factor (G-CSF) has been shown to support the growth of multipotential hematopoietic stem cells in addition to the cells of neutrophilic lineage. Philadelphia chromosome (Ph1)-positive leukemia has its origin in the hematopoietic stem cell. In the present study, we demonstrated that the proliferation of leukemic cells from chronic myeloid leukemia in blast crisis (CML-BC) and Ph1-positive acute lymphoblastic leukemia (ALL) cases is frequently stimulated with G-CSF in vitro. We next studied a total of 12 leukemic cell lines established from CML-BC (n= 6) and Ph1-positive acute leukemia (n= 6): four 'myeloid', five 'biphenotypic', and three 'lymphoid' types. All cell lines expressed G-CSF receptor (G-CSFR) in flow cytometric analysis, but their proliferative response to G-CSF in 3H-thymidine incorporation assay varied. The 'biphenotypic' cell lines expressed G-CSFR at higher levels and showed the most pronounced response to G-CSF. The 'lymphoid' cell lines showed intermediate G-CSFR expression with the modest response to G-CSF. Unexpectedly, 'myeloid' cell lines showed lower G-CSFR expression and lower G-CSF response compared with 'biphenotypic' cell lines. In three of four 'myeloid' cell lines, proliferation was partially inhibited by an addition of anti-G-CSF neutralizing monoclonal antibody into culture medium. Further, the % inhibition of 3H-thymidine uptake of cell lines positively correlated with the amount of their intracellular G-CSF measured by enzyme immunoassay, suggesting an autocrine growth mechanism via the G-CSF/G-CSFR interaction. These results suggest that G-CSF play an important role in the growth regulation of leukemia cells from Ph1-positive acute leukemia and CML-BC.
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PMID:Participation of granulocyte colony-stimulating factor in the growth regulation of leukemia cells from Philadelphia chromosome-positive acute leukemia and blast crisis of chronic myeloid leukemia. 1094 33

The arrest of differentiation is a feature of both chronic myelogenous leukemia cells in myeloid blast crisis and myeloid precursors that ectopically express the p210BCR-ABL oncoprotein; however, its underlying mechanisms remain poorly understood. Here we show that expression of BCR-ABL in myeloid precursor cells leads to transcriptional suppression of the granulocyte colony-stimulating factor receptor G-CSF-R (encoded by CSF3R), possibly through down-modulation of C/EBPalpha-the principal regulator of granulocytic differentiation. Expression of C/EBPalpha protein is barely detectable in primary marrow cells taken from individuals affected with chronic myeloid leukemia in blast crisis. In contrast, CEBPA RNA is clearly present. Ectopic expression of C/EBPalpha induces granulocytic differentiation of myeloid precursor cells expressing BCR-ABL. Expression of C/EBPalpha is suppressed at the translational level by interaction of the poly(rC)-binding protein hnRNP E2 with CEBPA mRNA, and ectopic expression of hnRNP E2 in myeloid precursor cells down-regulates both C/EBPalpha and G-CSF-R and leads to rapid cell death on treatment with G-CSF (encoded by CSF3). Our results indicate that BCR-ABL regulates the expression of C/EBPalpha by inducing hnRNP E2-which inhibits the translation of CEBPA mRNA.
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PMID:BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. 1175 85

The clinical progression of chronic myeloid leukemia (CML) from chronic phase to blast crisis is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes. This study was undertaken to investigate the influence of Bcr-Abl and of the small molecule Abl tyrosine-kinase inhibitor imatinib mesylate on granulocyte colony-stimulating factor (G-CSF)-induced neutrophilic differentiation. We show that differentiation of 32Dcl3 cells into mature granulocytes is accompanied by the increased expression of the antigens macrophage adhesion molecule-1 (Mac-1) and Gr-1, of the G-CSF receptor (G-CSFR), of myeloid transcription factors (CCAAT/enhancer-binding protein-alpha [C/EBPalpha], C/EBPepsilon, and PU.1), and of the cyclin-dependent kinase inhibitor p27(Kip1). In 32Dcl3 cells transfected with the bcr-abl gene (32D(Bcr-Abl)), G-CSF did not trigger either granulocytic differentiation or the up-regulation of C/EBPalpha, C/EBPepsilon, and the G-CSFR. This could be correlated to a defect in c-Myc down-regulation. In contrast, the up-regulation of PU.1 and p27(Kip1) by G-CSF was not affected by Bcr-Abl. Importantly, incubation of 32D(Bcr-Ablwt) cells with the kinase inhibitor imatinib mesylate prior to G-CSF stimulation completely neutralized the effects of Bcr-Abl on granulocytic differentiation and on C/EBPalpha and C/EBPepsilon expression. Taken together, the results suggest that the Bcr-Abl kinase induces a reversible block of the granulocytic differentiation program in myeloid cells by disturbing regulation of hematopoietic transcription factors such as C/EBPalpha and C/EBPepsilon.
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PMID:The effects of Bcr-Abl on C/EBP transcription-factor regulation and neutrophilic differentiation are reversed by the Abl kinase inhibitor imatinib mesylate. 1239 54

The death-associated protein kinase 2 (DAPK2) belongs to a family of Ca(2+)/calmodulin-regulated serine/threonine kinases involved in apoptosis. During investigation of candidate genes operative in granulopoiesis, we identified DAPK2 as highly expressed. Subsequent investigations demonstrated particularly high DAPK2 expression in normal granulocytes compared with monocytes/macrophages and CD34(+) progenitor cells. Moreover, significantly increased DAPK2 mRNA levels were seen when cord blood CD34(+) cells were induced to differentiate toward neutrophils in tissue culture. In addition, all-trans retinoic acid (ATRA)-induced neutrophil differentiation of two leukemic cell lines, NB4 and U937, revealed significantly higher DAPK2 mRNA expression paralleled by protein induction. In contrast, during differentiation of CD34(+) and U937 cells toward monocytes/macrophages, DAPK2 mRNA levels remained low. In primary leukemia, low expression of DAPK2 was seen in acute myeloid leukemia samples, whereas chronic myeloid leukemia samples in chronic phase showed intermediate expression levels. Lentiviral vector-mediated expression of DAPK2 in NB4 cells enhanced, whereas small interfering RNA-mediated DAPK2 knockdown reduced ATRA-induced granulocytic differentiation, as evidenced by morphology and neutrophil stage-specific maturation genes, such as CD11b, G-CSF receptor, C/EBPepsilon, and lactoferrin. In summary, our findings implicate a role for DAPK2 in granulocyte maturation.
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PMID:The death-associated protein kinase 2 is up-regulated during normal myeloid differentiation and enhances neutrophil maturation in myeloid leukemic cells. 1734 2

We have recently identified targetable mutations in CSF3R (GCSFR) in 60% of chronic neutrophilic leukemia (CNL) and atypical (BCR-ABL-negative) chronic myeloid leukemia (aCML) patients. Here we demonstrate that the most prevalent, activating mutation, CSF3R T618I, is sufficient to drive a lethal myeloproliferative disorder in a murine bone marrow transplantation model. Mice transplanted with CSF3R T618I-expressing hematopoietic cells developed a myeloproliferative disorder characterized by overproduction of granulocytes and granulocytic infiltration of the spleen and liver, which was uniformly fatal. Treatment with the JAK1/2 inhibitor ruxolitinib lowered the white blood count and reduced spleen weight. This demonstrates that activating mutations in CSF3R are sufficient to drive a myeloproliferative disorder resembling aCML and CNL that is sensitive to pharmacologic JAK inhibition. This murine model is an excellent tool for the further study of neutrophilic myeloproliferative neoplasms and implicates the clinical use of JAK inhibitors for this disease.
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PMID:The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibition. 2408 59

Disease-specific mutations facilitate diagnostic precision and drug target discovery. In myeloproliferative neoplasms (MPN), this is best exemplified by the chronic myeloid leukemia-associated BCR-ABL1. No other mutation in MPN has thus far shown a similar degree of diagnostic accuracy or therapeutic relevance. However, JAK2 and KIT mutations are detected in more than 90% of patients with polycythemia vera and systemic mastocytosis, respectively, and are therefore used as highly sensitive clonal markers in these diseases. JAK2 and MPL mutations also occur in essential thrombocythemia (ET) and primary myelofibrosis (PMF), but their diagnostic value is limited by suboptimal sensitivity and specificity. The molecular diagnostic gap in JAK2/MPL-unmutated ET/PMF is now partially addressed by the recent discovery of calreticulin (CALR) mutations in the majority of such cases. However, bone marrow morphology remains the central diagnostic platform and is essential for distinguishing ET from prefibrotic PMF and diagnosing patients those do not express JAK2, MPL or CALR (triple-negative). The year 2013 was also marked by the description of CSF3R mutations in the majority of patients with chronic neutrophilic leukemia (CNL). Herein, we argue for the inclusion of CALR and CSF3R mutations in the World Health Organization classification system for ET/PMF and CNL, respectively.
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PMID:An overview on CALR and CSF3R mutations and a proposal for revision of WHO diagnostic criteria for myeloproliferative neoplasms. 2444 Dec 92

Mutations in CSF3R (colony-stimulating factor 3 receptor) are frequent oncogenic drivers in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). Here we describe a 75 year old man who was diagnosed with CSF3R-T618I-positive atypical CML. He presented with leukocytosis, anemia, and thrombocytopenia and developed massive splenomegaly and severe constitutional symptoms. Hydroxyurea was given over a 6 month period but failed to provide any measureable clinical benefit. Eventually, he was treated with ruxolitinib, an FDA-approved JAK1/2 inhibitor, which resulted in dramatic improvement of his blood counts. He also had significant reduction of spleen volume and constitutional symptoms. This case highlights the need for a clinical trial to interrogate JAK1/2 as a potential molecular target in CNL and aCML in patients with or without CSF3R mutation. A clinical trial evaluating the safety and efficacy of ruxolitinib for this patient population is registered at ClinicalTrials.gov (NCT02092324).
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PMID:Significant clinical response to JAK1/2 inhibition in a patient with CSF3R-T618I-positive atypical chronic myeloid leukemia. 2518 Jan 55


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