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

A human yeast artificial chromosome (YAC) library was screened by polymerase chain reaction with oligonucleotide primers defined for DNA sequences of the BCR gene and the protooncogenes c-raf-1, c-fms, and c-erbB-2. Alu-PCR-generated human DNA sequences were obtained from the respective YAC clones and used for fluorescence in situ hybridization experiments under suppression conditions. After chromosomal in situ suppression hybridization to GTG-banded human prometaphase chromosomes, seven of nine initially isolated YAC clones yielded strong signals exclusively in the chromosome bands containing the respective genes. Two clones yielded additional signals on other chromosomes and were excluded from further tests. The band-specific YACs were successfully applied to visualize specific structural chromosome aberrations in peripheral blood cells from patients with myelodysplasia exhibiting del(5)(q13q34), chronic myeloid leukemia and acute lymphocytic leukemia with t(9;22)(q34;q11), acute promyelocytic leukemia (M3) with t(15;17)(q22;q21), and in a cell line established from a proband with the constitutional translocation t(3;8)(p14.2;q24). In addition to the analysis of metaphase spreads, we demonstrate the particular usefulness of these YAC clones in combination with whole chromosome painting to analyze specific chromosome aberrations directly in the interphase nucleus.
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PMID:Metaphase and interphase cytogenetics with Alu-PCR-amplified yeast artificial chromosome clones containing the BCR gene and the protooncogenes c-raf-1, c-fms, and c-erbB-2. 156 26

Cytologic and cytogenetic results obtained from patients fulfilling the FAB criteria for the diagnosis of acute nonlymphocytic leukemia (ANLL) of megakaryocytic lineage (ANLL-M7) are reported. Eleven cases were de novo ANLL-M7, of whom three presented with acute myelofibrosis. Four cases were megakaryoblastic transformations of chronic myelogenous leukemia (two cases), refractory anemia with excess of blasts (one case), and polycythemia vera (one case). Four patients showed a minority of granular blasts, with occasional Auer rods in one. Positive myeloperoxidase and/or sudan black-B stainings and CD13 positivity in these cases were consistent with the presence of a myeloid involvement. Morphologic evidence of associated myelodysplastic features was detected in all evaluable patients with de novo ANLL-M7. These cytologic findings indicate that ANLL-M7 may frequently represent a multilineage proliferation. Cytogenetic studies revealed -7/7q- and +8, alone or in combination with additional aberrations, in three cases each. Rearrangements involving bands 3q21 or 3q26 were seen in two patients and +21, as an additional aberration, in one. Other structural rearrangements all observed in a single patient were inv(16)(p13q22) at megakaryoblastic relapse with bone marrow eosinophilia, t(13;20)(q13 or 14;q11), del(20)(q11), and der(7)t(7;17)(p14;q22). Most breakpoints of these aberrations are located at bands frequently rearranged in malignant myeloid stem cell disorders. A review of 31 cases of the literature showed a frequent occurrence of -7/7q- and -5/5q- in ANLL-M7. Many of the chromosome aberrations so far described in ANLL-M7 appear to be shared by a spectrum of myeloid neoplasias and may be related to mechanisms conferring proliferative advantage to undifferentiated stem cells.
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PMID:Multipotent stem cell involvement in megakaryoblastic leukemia: cytologic and cytogenetic evidence in 15 patients. 279 Feb 2

Three cases with chromosome changes involving bands 7p14 or 7p15 and 11p15 are described: one was a Japanese female with an acute myelomonocytic leukemia, the second was a white female with a 10-year history of paroxysmal nocturnal hemoglobinuria who developed a myelodysplastic syndrome, and the third was a patient with Ph-negative atypical chronic myelogenous leukemia with trisomy 8 and a chromosome change involving bands 7p14 and 11p15. These cases possibly indicate that the t(7;11)(p14 or p15;p15) change may characterize a subset of human nonlymphocytic neoplasia.
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PMID:Translocation between chromosomes 7 and 11 in nonlymphocytic neoplasia. 347 6

Fluorescence in situ hybridization (FISH) and the reverse transcription-polymerase chain reaction (RT-PCR) were used to examine a patient presenting with acute myelogenous leukemia (AML) FAB M2, and a complex t(4;9;22)(p14;q34;q11.2). The patient's clinical course was characterized by an aggressive leukemia, resistant to intensive therapy including allogeneic bone marrow transplantation. FISH analysis, using two chromosome painting probes and a BCR/ABL specific probe, confirmed the cytogenetic observation of a 22q11.2-->4p14 and a 4p14-->9q34 exchange, and revealed the presence of a 9q34-->22q11.2, respectively. In addition, RT-PCR demonstrated the presence of a BCR/ABL transcript derived from the major breakpoint cluster region (M-bcr) of the BCR gene. This transcript has been shown to generate an active 210 kDa tyrosine kinase protein more commonly observed in chronic myelogenous leukemia. Because the presentation of AML with this ABL-->BCR fusion product is a rare event, it would seem likely that the additional complex chromosomal rearrangement involving chromosomes 4, 9, and 22 played a role in the aggressive presentation and clinical behavior of this patient's leukemia.
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PMID:Complex chromosome 4, 9, and 22 rearrangement in a patient presenting with AML-FAB M2. 907 96

Over the last decade, a growing number of tumor suppressor genes have been discovered to play a role in tumorigenesis. Mutations of p53 have been found in hematological malignant diseases, but the frequency of these alterations is much lower than in solid tumors. These mutations occur especially as hematopoietic abnormalities become more malignant such as going from the chronic phase to the blast crisis of chronic myeloid leukemia. A broad spectrum of tumor suppressor gene alterations do occur in hematological malignancies, especially structural alterations of p15(INK4A), p15(INK4B) and p14(ARF) in acute lymphoblastic leukemia as well as methylation of these genes in several myeloproliferative disorders. Tumor suppressor genes are altered via different mechanisms, including deletions and point mutations, which may result in an inactive or dominant negative protein. Methylation of the promoter of the tumor suppressor gene can blunt its expression. Chimeric proteins formed by chromosomal translocations (i.e. AML1-ETO, PML-RARalpha, PLZF-RARalpha) can produce a dominant negative transcription factor that can decrease expression of tumor suppressor genes. This review provides an overview of the current knowledge about the involvement of tumor suppressor genes in hematopoietic malignancies including those involved in cell cycle control, apoptosis and transcriptional control.
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PMID:Tumor suppressor genes in normal and malignant hematopoiesis. 1203 83

The frequency and mechanism of p16(INK4A) and p14(ARF) gene alterations were studied in cell samples from 30 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML), both at diagnosis and at the onset of the accelerated phase (AP) of the disease. No alterations in the p16(INK4A) or p14(ARF) genes were found in any of the chronic phase (CP) samples. DNA sequencing analyses detected p16(INK4A) or p14(ARF) mutations in 17 AP samples. All mutations were heterozygous without loss of the other allele. Aberrant methylation of the p16(INK4A) or p14(ARF) promoters was found in 14 of 30 AP samples. The most common situation was the simultaneous methylation of both promoters. Our data indicate that p16(INK4A) and p14(ARF) are primary targets for inactivation by promoter methylation in the acceleration of CML. Transcriptional silencing of the p16(INK4A) and p14(ARF) genes may be important in the conversion of CML from the CP to the AP.
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PMID:Frequent methylation of p16INK4A and p14ARF genes implicated in the evolution of chronic myeloid leukaemia from its chronic to accelerated phase. 1455 20

TMEM16A (FLJ10261 or ORAOV2) gene within the CCND1-FGF4-EMS1 amplicon at human chromosome 11q13.3 encodes transmembrane protein homologous to TMEM16B (C12orf3), TMEM16C (C11orf25), and TMEM16D (FLJ34272). Here, we identified novel TMEM16 family genes by using bioinformatics. Novel genes corresponding to DKFZp451A148 cDNA (AL833271.1) and 9330162L24 cDNA (AK034197.1) were designated human TMEM16E gene and mouse Tmem16e gene, respectively. Novel genes corresponding to DKFZp451M105 cDNA (AL832340.1) and F730003B03 cDNA (BC060732.1) were designated human TMEM16F gene and mouse Tmem16f gene, respectively. NELL1-TMEM16E locus at human chromosome 11p15.1-p14.3 and NELL2-TMEM16F locus at human chromosome 12q12 were paralogous regions within the human genome. TMEM16E mRNA was expressed in testis and pancreatic islet, while TMEM16F mRNA was expressed in embryonic stem cell, fetal liver, retina, chronic myelogenous leukemia, and intestinal cancer. TMEM16E (913 aa) and TMEM16F (892 aa) showed 50.3% total-amino-acid identity. Eight-transmembrane domains were identified within TMEM16E and TMEM16F proteins by using the TMHMM2 program. Phylogenetic analysis revealed that TMEM16E and TMEM16F constitute a subfamily among TMEM16 family proteins. TM16H1 domain around transmembrane domain 1 (TM1)-TM2, TM16H2 domain around TM5, and TM16H3 domain around TM6-TM7 were identified as conserved regions among TMEM16 family proteins. TMEM16 family members were eight-transmenbrane proteins with TM16H1-TM16H3 domains and a conserved Asn glycosylation site. This is the first report on TMEM16E and TMEM16F genes.
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PMID:Identification and characterization of TMEM16E and TMEM16F genes in silico. 1506 59

Chronic myelogenous leukemia (CML) evolves from an indolent chronic phase (CP) characterized by the Philadelphia chromosome. Without effective therapy, it progresses to an accelerated phase (AP) and eventually to a fatal blast crisis (BC). To identify the genes involved in stage progression in CML, we performed a genomewide screening of DNA copy number changes in a total of 55 CML patients in different stages with the use of the high-resolution array-based comparative genomic hybridization (array CGH) technique. We constructed Human 1M arrays that contained 3,151 bacterial artificial chromosome (BAC) DNAs, allowing for an average resolution of 1.0 Mb across the entire genome. In addition to common chromosomal abnormalities, array CGH analysis unveiled a number of novel copy number changes. These alterations included losses in 2q26.2-q37.3, 5q23.1-q23.3, 5q31.2-q32, 7p21.3-p11.2, 7q31.1-q31.33, 8pter-p12(p11.2), 9p, and 22q13.1-q13.31 and gains in 3q26.2-q29, 6p22.3, 7p15.2-p14.3, 8p12, 8p21.3, 8p23.2, 8q24.13-q24.21, 9q, 19p13.2-p12, and 22q13.1-q13.32 and occurred at a higher frequency in AP and BC. Minimal copy number changes affecting even a single BAC locus were also identified. Our data suggests that at least a proportion of CML patients carry still-unknown cryptic genomic alterations that could affect a gene or genes of importance in the disease progression of CML. This article contains Supplementary Material available at http://www.interscience.wiley.com/jpages/1045-2257/suppmat.
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PMID:Genomewide screening of DNA copy number changes in chronic myelogenous leukemia with the use of high-resolution array-based comparative genomic hybridization. 1642 96

Expression of p14(ARF) and p16(INK4a) tumor suppressor genes was investigated in 109 patients with chronic myeloid leukemia (CML). The p14(ARF) and p16(INK4a) mRNA levels were significantly low in patients in chronic phase (CP) at presentation and high in patients treated with interferon-alpha (IFN-alpha), especially in non-responders. A moderate overexpression of p14(ARF) with a normal expression of p16(INK4a) was observed in imatinib-resistant patients. Although protein expression did not consistently match mRNA levels, a role for the two cell cycle regulators in the IFN-alpha signaling pathway is suggested as well as a relation with the resistance to IFN-alpha or imatinib therapy.
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PMID:Expression of the cell cycle regulators p14(ARF) and p16(INK4a) in chronic myeloid leukemia. 1653 30

Senescence and apoptosis programs governed by the Rb and p53 signaling networks can counter tissue stem cell self-renewal. A master regulator of Rb and p53 is the INK4-ARF (CDKN2A/B) locus that encodes two CDK inhibitors, p16(INK4A) and p15(INK4B), that maintain Rb in its active, hypophosphorylated form, and p14(ARF) (p19(Arf) in mice), that inhibits Mdm2 and activates p53. The INK4-ARF genes are epigenetically silenced in hematopoietic stem cells but become poised to respond to oncogenic stress as blood cells differentiate. Inactivation of INK4-ARF endows differentiated cells with an inappropriate self-renewal capacity, a defining feature of cancer cells. In BCR-ABL-induced (Philadelphia chromosome-positive [Ph(+)]) leukemias, INK4-ARF deletions frequently occur in clinically aggressive acute lymphoblastic leukemias (Ph(+) ALLs) but are not seen in more indolent Ph(+) chronic myelogenous leukemia (CML) or in CML myeloid blast crisis. Mouse modeling of Ph(+) ALL reveals that Arf inactivation attenuates responsiveness to targeted BCR-ABL kinase inhibitors, enhances the maintenance of leukemia-initiating cells within the hematopoietic microenvironment, and facilitates the emergence of malignant clones that harbor drug-resistant BCR-ABL kinase mutations. Thus, although BCR-ABL mutations typify drug resistance in both CML and Ph(+) ALL, loss of INK4-ARF in Ph(+) ALL enhances disease aggressiveness and undermines the salutary effects of targeted therapy.
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PMID:The INK4-ARF (CDKN2A/B) locus in hematopoiesis and BCR-ABL-induced leukemias. 1902 87


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