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)

The functions of JunB during myelopoiesis were studied in vivo. Transgenic mice specifically lacking JunB expression in the myeloid lineage (junB(-/-)Ubi-junB mice) develop a transplantable myeloproliferative disease eventually progressing to blast crisis, which resembles human chronic myeloid leukemia. Similarly, mice reconstituted with ES cell-derived junB-/- fetal liver cells also develop a myeloproliferative disease. In both cases, the absence of JunB expression results in increased numbers of granulocyte progenitors, which display enhanced GM-CSF-mediated proliferation and extended survival, associated with changes in the expression levels of the GM-CSFalpha receptor, the anti-apoptotic proteins Bcl2 and Bclx, and the cell cycle regulators p16(INK4a) and c-Jun. Importantly, ectopic expression of JunB fully reverts the immature and hyperproliferative phenotype of JunB-deficient myeloid cells. These results identify JunB as a key transcriptional regulator of myelopoiesis and a potential tumor suppressor gene.
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PMID:Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. 1116 37

Protein phosphatase-2A (PP2A) is one of the major cellular serine-threonine phosphatases and is involved in the regulation of cell homeostasis through the negative regulation of signaling pathways initiated by protein kinases. As several cancers are characterized by the aberrant activity of oncogenic kinases, it was not surprising that a phosphatase like PP2A has progressively been considered as a potential tumor suppressor. Indeed, multiple solid tumors (e.g. melanomas, colorectal carcinomas, lung and breast cancers) present with genetic and/or functional inactivation of different PP2A subunits and, therefore, loss of PP2A phosphatase activity towards certain substrates. Likewise, impaired PP2A phosphatase activity has been linked to B-cell chronic lymphocytic leukemia, Philadelphia-chromosome positive acute lymphoblastic leukemia and blast crisis chronic myelogenous leukemia. Remarkably, drugs such as forskolin, 1,9-dideoxy-forskolin and FTY720 which lead to PP2A activation effectively antagonize leukemogenesis in both in vitro and in vivo models of these cancers. Thus, PP2A is now in the spotlight as a highly promising drugable target for the development of a new series of anticancer agents potentially capable of overcoming drug-resistance induced in patients by continuous exposure to kinase inhibitor monotherapy. Herein, we review current knowledge of PP2A biology and function with particular emphasis on its tumor suppressor activity and possible therapeutic implications in cancer.
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PMID:Protein phosphatase 2A (PP2A), a drugable tumor suppressor in Ph1(+) leukemias. 1821 49

Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673-12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.
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PMID:HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients. 2348 77

Retroviral models have tremendously contributed to our understanding of CML development and have been indispensable for preclinical drug testing which facilitated the implementation of a targeted therapy. The retroviral insertion of Bcr-Abl into mice that are genetically depleted for a potential tumor suppressor is a tool to test for a specific gene function in Bcr-Abl disease. Here we describe how to generate a Bcr-Abl retrovirus that is subsequently used for infection of primary murine BM cells, which are genetically depleted for a potential tumor suppressor gene. We will suggest control experiments and outline further methods that are required to allow for assessment of disease development upon tumor suppressor knockout in CML.
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PMID:Tumor Suppressor Analysis in CML. 2758 Nov 41

Circadian clock genes (CCGs) are reported to serve pivotal roles in regulating the development of certain tumors, including lung cancer and colon cancer . However, their expression patterns and function in chronic myeloid leukemia (CML) remains poorly understood. The present study aimed to investigate the expression and function of circadian clock gene Period2 (Per2) in human CML. Per2 expression levels in neutrophils isolated from patients with CML and healthy donors were measured via reverse transcription-quantitative PCR. Subsequently, through lentivirus transduction, Per2 was stably overexpressed in human CML cell line KCL22 cells, which were injected into nude mice to investigate the in vivo role of Per2 by measuring CML tumor size and weight. Additionally, Per2 expression levels in patients with acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL) were analyzed by re-analyzing microarray data in the Gene Expression Omnibus database. Per2 expression was significantly lower in neutrophils isolated from patients with CML patients compared with healthy donors, and was negatively correlated with the expression level of c-Myc. Similarly, patients with AML or CLL displayed lower Per2 expression levels compared with healthy controls. Per2 overexpression inhibited KCL22 cell proliferation in nude mice and in vitro, and induced cell cycle arrest at the G1 phase. By contrast, the results also indicated that KCL22 cell apoptosis was not regulated by Per2. The present study identified Per2 as a potential tumor suppressor in human CML.
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PMID:Circadian clock gene Period2 suppresses human chronic myeloid leukemia cell proliferation. 3309 85