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)

Using fluorescence in situ hybridization probes, obtained from bacterial artificial chromosome (BAC) libraries that relate to sequences either side of the BCR and ABL genes, this study characterized four chronic myeloid leukemia cases with cryptic BCR-ABL rearrangements. Each case showed evidence of a different underlying mechanism: one case showed a microinsertion of BCR into ABL, another a microinsertion of ABL into BCR, and the third showed a complex rearrangement including deletion of adjacent flanking sequences, consistent with the reverse translocation model of cryptic rearrangement. The fourth case also showed evidence of a more complex rearrangement involving chromosome 1.
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PMID:Fluorescence in situ hybridization characterization of different cryptic BCR-ABL rearrangements in chronic myeloid leukemia. 1557 98

The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib.
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PMID:Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32). 1571

Several groups have demonstrated that a submicroscopic gene deletion in Ph+ chronic myelogenous leukemia (CML) is associated with a poor prognosis and reduced response to treatment. To assess the variation between detection methods in the interpretation of a submicroscopic gene deletion, we performed an extra signal (ES)-FISH BCR/ABL and double-FISH (D-FISH) BCR/ABL on frozen bone marrow cells from 79 patients with CML (63 in the chronic phase, 6 in the accelerated phase, and 10 in blast crisis) and 30 patients with a BCR/ABL-negative myeloproliferative disorder as determined by RT-PCR. The normal cutoff values were 0.22% for ES-FISH and 0.25% for D-FISH. The cutoff values for false-positive signals from a juxtaposition of the BCR and ABL gene were 11% in ES-FISH and 13% in D-FISH. Of the 14 patients who showed an ABL gene deletion by ES-FISH, 5 had an ABL deletion only, 5 had both a BCR and an ABL deletion, but 4 proved to have a classic BCR/ABL rearrangement without a submicroscopic deletion, as determined by D-FISH. Discrepant results between ES- and D-FISH were observed in 12 of the 79 patients (15.8%), and the main causes of a discrepancy were a false-positive ABL deletion (4 of 12, 33%), a variant Philadelphia chromosome (3 of 12, 25%), an inversion of derivative chromosome 9 at the very breakpoint of the ABL gene (9q32) (1 of 12, 8.3%), a cryptic variant Ph chromosome (1 of 12, 8.3%), and a marker chromosome (1 of 12, 8.3%). Although there was no significant difference in the sensitivity for the detection of the fusion signal between ES- and D-FISH, ES-FISH showed a high percentage of cells with false-positive fusion signals (1 orange, 1 green, 1 yellow), which makes it difficult to interpret the submicroscopic ABL deletion. In conclusion, an interpretation of the submicroscopic deletions of the BCR or ABL gene should not depend on ES-FISH.
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PMID:Interpretation of submicroscopic deletions of the BCR or ABL gene should not depend on extra signal-FISH: problems in interpretation of submicroscopic deletion of the BCR or ABL gene with extra signal-FISH. 1572 38

This is the first report of e6a2 and e1a2 BCR/ABL1 positive chronic myeloid leukemia (CML) with cryptic deletions of the 5'ABL1 and 3'BCR in separate clones which differ in genomic regions of the deleted der(9). Both deletions were detected throughout monitoring. Imatinib mesylate stabilized this CML with rare genetic aberrations for a relatively long time.
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PMID:e6a2 BCR/ABL1 fusion with cryptic der(9)t(9;22) deletions in a patient with chronic myeloid leukemia. 1607 18

The potential of the transformed (leukemic) multipotential hematopoietic cell to differentiate and mature along any myeloid lineage forms the basis for the phenotypic classification of acute and chronic myelogenous leukemia. Although most cases of leukemia can be classified phenotypically by the dominant lineage expressed, the genotype within each phenotype is heterogeneous. Thus, covert genetic factors, cryptic mutations, and/or polymorphisms may interact with the seminal transforming genetic mutations to determine phenotype. The phenotype usually is expressed sufficiently to determine the lineage that is dominant in the leukemic clone by light microscopic examination, by cytochemistry of blood and marrow cells, and by immunophenotyping. The basis for the frequency of the AML phenotypes is unclear, although there is a rough concordance with the frequency of marrow precursor cells of different lineages. The least common AML phenotypes are a reflection of the least common blood or marrow cell lineages: acute basophilic, acute mast cell, acute eosinophilic, and acute myeloid dendritic cell leukemia. We discuss the features of these uncommon phenotypes and review the criteria used for their diagnosis.
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PMID:Uncommon phenotypes of acute myelogenous leukemia: basophilic, mast cell, eosinophilic, and myeloid dendritic cell subtypes: a review. 1620 63

Patients presenting with thrombocytosis require thorough clinical and laboratory evaluation to determine whether they suffer from essential thrombocythemia or another myeloproliferative disorder. This distinction becomes increasingly relevant as targeted agents become available to treat specific myeloproliferative diseases. Cytogenetic testing plays a major role in this analysis. This study presents a patient with Philadelphia chromosome positive (Ph + ) thrombocytosis and a cryptic der(9q)t(5;9)t(9;22) not found by conventional cytogenetics, whose disease progressed within 2 years to typical myeloblastic crisis of CML. It discusses the entity of Ph + ET, the utility of molecular cytogenetic testing in the diagnosis of this unusual disease entity and the importance of cytogenetic testing in the prognosis of ET.
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PMID:Variant translocation with a deletion of derivative (9q) in a case of Philadelphia chromosome positive (Ph +) essential thrombocythemia (ET), a variant of chronic myelogenous leukemia (CML) with a poor prognosis. 1626 84

The BCR/ABL gene rearrangement is the causing factor in chronic myeloid leukemia (CML). In most cases, it is cytogenetically visualized as a translocation between chromosomes 9 and 22, known as the Philadelphia (Ph) translocation. About 5-10% of CML patients lack cytogenetic evidence of the Ph translocation but show BCR/ABL fusion by fluorescence in situ hybridization (FISH) or reverse transcriptase-polymerase chain reaction. Deletions around the breakpoints on the derivative 9 including ABL and or BCR sequences occur in 10-15% of Ph+ CML patients and are thought to have prognostic significance. We describe two patients with CML and normal karyotype in whom cryptic rearrangements involving chromosomes 9 and 22 resulted in the causative BCR/ABL gene. FISH with a three-color probe combination revealed BCR/ABL fusion on chromosome 9 without deletion in one patient; the other patient had BCR/ABL on chromosome 22 with an associated derivative 9 deletion. We discuss the proposed mechanisms in the formation of BCR/ABL in the setting of a normal karyotype. Some authors reported that patients with the chimeric gene located on the derivative 9 have a poor clinical course. We suggest that deletion rather than location of the chimeric gene alone is more likely to be associated with prognosis.
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PMID:BCR/ABL rearrangement in two cases of Philadelphia chromosome negative chronic myeloid leukemia: deletion on the derivative chromosome 9 may or not be present. 1633 61

Chronic myeloproliferative diseases (CMPDs) are characterized by the abnormal proliferation and survival of one or more myeloid cell types. The archetype of this class of hematological diseases is chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia (Ph) chromosome, the result of t(9;22)(q34;q11), and the associated BCR-ABL1 oncogene. Some of the Ph-negative myeloproliferative diseases are characterized by other chromosomal translocations involving a variety of tyrosine kinase genes, including ABL1, ABL2, PDGFRA, PDGFRB, FGFR1, and JAK2. The majority of Ph-negative CMPDs, however, such as chronic eosinophilic leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are not characterized by the presence of recurrent chromosomal abnormalities. Recent studies have identified the FIP1L1-PDGFRA fusion gene, generated due to a small cryptic deletion on chromosome 4q12, and the activating V617F mutation in JAK2 in a significant fraction of Ph-negative CMPDs. These results show that abnormalities in tyrosine kinase genes are central to the molecular pathogenesis of CMPDs. Genome-wide screenings to identify novel tyrosine kinase abnormalities in CMPDs may contribute to further improvement of the diagnosis and the treatment of these diseases.
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PMID:Chronic myeloproliferative disorders: a tyrosine kinase tale. 1634 Oct 34

The virtually obligatory presence of the Philadelphia chromosome may suggest a causal homogeneity, but chronic myelogenous leukemia (CML) is a clinically heterogeneous disease. This may be a consequence of the variable BCR breakpoints on chromosome 22 and of nonrandom secondary chromosomal abnormalities. We present the case of a boy, age 12, investigated in blastic phase of CML. Karyotyping with conventional and multiplex fluorescence in situ hybridization (FISH and M-FISH) karyotyping, complemented with reverse transcriptase-polymerase chain reaction, identified a variant Philadelphia translocation t(9;14;22)(q34;q32;q11) involving a cryptic BCR/ABL fusion with formation of the p190(Bcr-Abl) oncoprotein. M-FISH revealed also an unbalanced jumping translocation of 17q11 approximately qter alternatively present on chromosomes 14 or 20, apparently hithertofore unreported in hematological malignancies. Another secondary aberration, dup(3)(q25q28), was revealed by multipoint interphase FISH (mpI-FISH). Gain of this region is known in adult hematological malignancies and solid tumors, suggesting its general involvement in tumor initiation or progression (or both), regardless of tissue origin.
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PMID:Jumping translocation of 17q11 approximately qter and 3q25 approximately q28 duplication in a variant Philadelphia t(9;14;22)(q34;q32;q11) in a childhood chronic myelogenous leukemia. 1636 67

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


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