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)

The BCR/ABL gene fusion, the hallmark of chronic myelogenous leukemia (CML) is generated in 2-10% of patients by a variant Ph translocation involving 9q34, 22q11.2, and one or more additional genomic regions. The objective of this study was the characterization by conventional and molecular cytogenetics of complex variant Ph translocations present at diagnosis. FISH studies were performed in 7 cases using the LSI BCR/ABL ES probe allowing the detection of the fusion BCR/ABL gene on the Ph chromosome in all of them and 9q34 deletions in 2 cases. Three cryptic complex rearrangements were detected by FISH studies. The third and the fourth chromosome regions involved in the 8 complex variant translocations were: 1q21, 1p36, 5q31, 11q13, 12q13, 12p13, and 20q12. In conclusion, FISH studies have been useful in the detection of the BCR/ABL rearrangements and 9q34 deletions, and to identify complex rearrangements that differ from the ones previously established by conventional cytogenetics.
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PMID:Studies of complex Ph translocations in cases with chronic myelogenous leukemia and one with acute lymphoblastic leukemia. 1661 17

Self-tumor Ags that elicit antitumor immune responses in responses to IFN-alpha stimulation remain poorly defined. We screened a human testis cDNA library with sera from three polycythemia vera patients who responded to IFN-alpha and identified a novel Ag, MPD6. MPD6 belongs to the group of cryptic Ags without conventional genomic structure and is encoded by a cryptic open reading frame located in the 3'-untranslated region of myotrophin mRNA. MPD6 elicits IgG Ab responses in a subset of polycythemia vera patients, as well as patients with chronic myelogenous leukemia and prostate cancer, suggesting that it is broadly immunogenic. The expression of myotrophin-MPD6 transcripts was up-regulated in some tumor cells, but only slightly increased in K562 cells in response to IFN-alpha treatment. By using bicistronic reporter constructs, we showed that the translation of MPD6 was mediated by a novel internal ribosome entry site (IRES) upstream of the MPD6 reading frame. Furthermore, the MPD6-IRES-mediated translation, but not myotrophin-MPD6 transcription, was significantly up-regulated in response to IFN-alpha stimulation. These findings demonstrate that a novel IRES-mediated mechanism may be responsible for the translation of unconventional self-Ag MPD6 in responsive to IFN-alpha stimulation. The eliciting antitumor immune response against unconventional Ag MPD6 in patients with myeloproliferative diseases suggests MPD6 as a potential target of novel immunotherapy.
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PMID:An unconventional antigen translated by a novel internal ribosome entry site elicits antitumor humoral immune reactions. 1698 33

The expression of the chimeric BCR/ABL1 fusion gene resulting from t(9;22)(q34;q11) in chronic myelogenous leukemia (CML) is necessary for malignant transformation, but not sufficient to maintain disease progression. The appearance of various chromosomal and molecular alterations in the accelerated and terminal phase of CML is well documented, but evidence for causal relationship is largely lacking. We carried out a genome wide screening at a resolution of 1 Mb of 54 samples at different stages of CML together with 12 CML cell lines and found that disease progression is accompanied by a spectrum of recurrent genome imbalances. Among the most frequent are losses at 1p36, 5q21, 9p21, and 9q34 and gains at 1q, 8q24, 9q34, 16p, and 22q11, all of which were located with higher precision within the genome than previously possible. These genome imbalances are unique to CML cases with clinically manifested or suspected accelerated/blast stage alike, but not seen in chronic phase samples. Previously unrecognized cryptic imbalances occurring within the Ph-chromosome were also detected, although further scrutiny is required to pin-point gene involvement and seek association with disease features. Importantly, some of these imbalances were seen in the CD34(+) cells but not in the whole BM samples of patients in accelerated phase. Taken together, these findings highlight the potential of screening CD34(+) cells for genome wide imbalances associated with disease progression. Finally, the numerous single copy number variations recorded, many unique to this cohort of patients, raise the possible association of genome polymorphism and CML.
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PMID:Genomic profile of chronic myelogenous leukemia: Imbalances associated with disease progression. 1769 94

Imatinib, a selective ABL kinase inhibitor has improved therapeutic outcome in patients with Philadelphia positive chronic or acute leukemia. In the present study, we describe a 56-year-old male with Philadelphia chromosome positive acute lymphocytic leukemia (ALL) who was treated with up-front single agent imatinib and achieved complete hematologic, cytogenetic and molecular remission. At relapse 11 months later, new chromosomal translocations involving chromosomes 1, 7 and 4 and cryptic addition to chromosome 11 were identified in Ph+ cells and the patient had rapid deterioration with progressive disease. The significance of additional chromosomal abnormalities in imatinib treated patients and secondary chromosomal abnormalities in Philadelphia positive chronic myeloid leukemia and ALL are discussed briefly in this report.
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PMID:Clonal evolution with +11q 13, t(1;7) and t(1;4) at relapse in a patient with Ph positive acute lymphocytic leukemia (ALL) treated with single agent front line imatinib followed by dasatinib. 1785 64

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.
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PMID:RUNX1 DNA-binding mutations and RUNX1-PRDM16 cryptic fusions in BCR-ABL+ leukemias are frequently associated with secondary trisomy 21 and may contribute to clonal evolution and imatinib resistance. 1820 28

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence in leukemic stem cells of the Philadelphia chromosome (Ph) and the formation of the BCR-ABL1 fusion. Untreated, the disease progresses to accelerate phase and blast crisis in which hematopoietic differentiation has become arrested. CML progression is frequently associated with cytogenetic evidence of clonal evolution, defined as additional chromosomal aberrations. We here report a CML resistant to tyrosine kinase inhibitors that rapidly progressed to blastic phase. At this time, array CGH performed on CD34(+) cells revealed cryptic partial deletions of both PRDM16 and RUNX1 and duplication of the der(21) chromosome. These genomic rearrangements were confirmed by FISH with probes targeting the deletion on chromosome 21 (24 kb), and with BAC probes flanking the deletion on 1p36 (220 kb). However, no cryptic t(1;21)(p36;q22) and/or RUNX1-PRDM16 were detected, suggesting that these deletions are the residual hallmarks of a more complex mechanism of chromosomal rearrangement, as indicated by the additional inversion of the region bounded by 1p36.32 and 1p36.12 breaks. At the molecular level, these abnormalities lead to the overexpression of the PR-domain negative oncogenic isoform of PRDM16, associated with two deleted copies within the runt domain of C-teminal aberrant RUNX1. These events are not detectable by conventional cytogenetic and molecular strategies, and may be of underestimated frequency in disease progression.
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PMID:Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression? 1876 45

We report a rare cryptic ins(12;9)(p13;q34q34), a chromosomal abnormality involving the ABL1 (9q34) and the ETV6 (alias TEL; 12p13) genes, detectable only by fluorescence in situ hybridization (FISH), in a patient with Philadelphia-negative chronic myeloid leukemia (CML). Using reverse 4',6-diamidino-2-phenylindole banding on metaphase cells, FISH analysis with BCR/ABL dual-fusion and ETV6 break-apart probes showed that a third ABL signal was inserted into 12p, splitting the ETV6 signal into two adjacent signals. CML patients with an ABL1/ETV6 fusion historically have demonstrated a variable and sometimes transient response to treatment with imatinib mesylate, which was also the case in the present patient.
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PMID:Insertion (12;9)(p13;q34q34): a cryptic rearrangement involving ABL1/ETV6 fusion in a patient with Philadelphia-negative chronic myeloid leukemia. 1948 Sep 35

We herein report the findings of a 47-year-old Japanese female with chronic myeloid leukemia (CML) with a cryptic BCR-ABL1 transcript on chromosome 9 and a derivative chromosome 22 unrelated to BCR-ABL1. Although she achieved and continued to demonstrate a major molecular response to imatinib treatment following interferon-alpha, there was persistence of a derivative chromosome 22. A detailed chromosome/molecular studies, including serial karyotyping analysis, finally resulted in the karyotyping at the disease onset to be 47,XX,+del(22)(q11.2), with two genetic evens, namely a cryptic BCR-ABL1 transcript on chromosome 9 and derivative chromosome 22 unrelated to BCR-ABL1. This CML case with these two rare genetic events thus raises diagnostic issues such as the difficulty in making a concise evaluation of the chromosomal/molecular events and an accurate disease prognosis, as well as the difficulty in determining the disease remission status after treatment.
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PMID:Persistence of derivative chromosome 22 after achieving a major molecular response in chronic myeloid leukemia with a cryptic BCR-ABL1 fusion gene. 1999 64

Rearrangements of chromosome 3 involving bands 3q21 and 3q26 have been reported in about 2% of patients with acute myeloid leukemia, and rarely in myelodysplastic syndrome or chronic myelogenous leukemia (CML). To date, only six cases of inversion of both homologues have been reported. Loss of normal chromosome 3 and duplication of the inverted chromosome have been proposed as the most likely mechanism, but have not been shown experimentally. We present a 36-year-old male with an initial diagnosis of CML and resistance to imatinib mesylate. Chromosome analysis showed an inversion within the long arm of both homologues of chromosome 3 and an interstitial deletion within the long arm of one chromosome 7. The rearrangement of EVI1 locus on both homologues of chromosome 3 was confirmed by fluorescence in situ hybridization (FISH). Additional FISH studies showed a cryptic insertion of ABL1 into the BCR region, and subsequent duplication of the derivative chromosome 22. The single-nucleotide polymorphism array showed copy-neutral loss of heterozygosity on chromosomes 3 and 22, suggesting that a somatic repair mechanism is involved in the evolution of these genetic alterations. This case illustrates the complexity of genetic aberrations in neoplastic cells, and the value of array technology, used in concert with conventional cytogenetic methods, for a better understanding of the pathogenesis.
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PMID:Cytogenetic and molecular characterization of double inversion 3 associated with a cryptic BCR-ABL1 rearrangement and additional genetic changes. 2068 91

To ascertain genomic alterations associated with Imatinib resistance in chronic myeloid leukaemia, we performed high resolution genomic analysis of CD34(+) cells from 25 Imatinib (IM) resistant and 11 responders CML patients. Using patients' T-cells as reference, we found significant association between number of acquired cryptic copy number alterations (CNA) and disease phase (p=0.036) or loss of IM response for patients diagnosed in chronic phase (CP) (p=0.04). Recurrent cryptic losses were identified on chromosomes 7, 12 and 13. On chromosome 7, recurrent deletions of the IKZF1 locus were detected, for the first time, in 4 patients in CP.
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PMID:Genomic characterization of Imatinib resistance in CD34+ cell populations from chronic myeloid leukaemia patients. 2068 91


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