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 t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.
 ...
PMID:Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). 1044 Oct 11

The AML1 gene, situated in 21q22, is often rearranged in acute leukemias through t(8;21) translocation, t(12;21) translocation, or less often t(3;21) translocation. Recently, point mutations in the Runt domain of the AML1 gene have also been reported in leukemia patients. Observations for mutations of the Runt domain of the AML1 gene in bone marrow cells were made in 300 patients, including 131 with acute myeloid leukemia (AML), 94 with myelodysplastic syndrome (MDS), 28 with blast crisis chronic myeloid leukemia (CML), 3 with atypical CML, 41 with acute lymphoblastic leukemia (ALL), and 3 with essential thrombocythemia (ET). Forty-one of the patients had chromosome 21 abnormalities, including t(8;21) in 6 of the patients with AML, t(12;21) in 8 patients with ALL, acquired trisomy 21 in 17 patients, tetrasomy 21 in 7 patients, and constitutional trisomy 21 (Down syndrome) in 3 patients. A point mutation was found in 14 cases (4.7%), including 9 (22%) of the 41 patients with AML of the Mo type (MoAML) (none of them had detectable chromosome 21 rearrangement) and 5 (38%) of the 13 myeloid malignancies with acquired trisomy 21 (1 M1AML, 2 M2AML, 1 ET, and 1 atypical CML). In at least 8 of 9 mutated cases of MoAML, both AML alleles were mutated: 3 patients had different stop codon mutations of the 2 AML1 alleles, and 5 patients had the same missense or stop codon mutation in both AML1 alleles, which resulted in at least 3 of the patients having duplication of the mutated allele and deletion of the normal residual allele, as shown by FISH analysis and by comparing microsatellite analyses of several chromosome 21 markers on diagnosis and remission samples. In the remaining mutated cases, with acquired trisomy 21, a missense mutation of AML1, which involved 2 of the 3 copies of the AML1 gene, was found. Four of the 7 mutated cases could be reanalyzed in complete remission, and no AML1 mutation was found, showing that mutations were acquired in the leukemic clone. In conclusion, these findings confirm the possibility of mutations of the Runt domain of the AML1 gene in leukemias, mainly in MoAML and in myeloid malignancies with acquired trisomy 21. AML1 mutations, in MoAML, involved both alleles and probably lead to nonfunctional AML1 protein. As AML1 protein regulates the expression of the myeloperoxidase gene, the relationship between AML1 mutations and Mo phenotype in AML will have to be further explored. (Blood. 2000;96:2862-2869)
 ...
PMID:High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2 alpha B gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. 1102 23

The pattern of occurrence of malignant disorders in people with Down's syndrome (DS) is unique and may serve as a model in the search for leukaemogenic genes and tumour suppressor genes on chromosome 21, since the risk of leukaemia is higher in individuals with DS than in non-DS individuals. Acute lymphoblastic leukaemia in DS shares many of the clinical characteristics of the same malignancy in other patients, and with current intensive therapy the long-term survival is similar. Myelodysplastic syndrome and acute myeloid leukaemia have unique clinical characteristics in these patients and are best described as a single disorder, termed myeloid leukaemia of DS. When these patients are treated intensively, they show better survival rates than patients without DS. This may be related to increased expression of genes on chromosome 21 contributing to increased chemosensitivity. Chronic myeloid leukaemia and chronic lymphocytic leukaemia occur less often than expected. With the exception of an increased risk of retinoblastoma, germ-cell tumours, and perhaps lymphomas, the risk of developing solid tumours is lower in both children and adults. Breast cancer is almost absent, and the risk of a second malignant disease after treatment for leukaemia also appears to be decreased. Increased susceptibility to apoptosis in DS may result in cell death rather than malignant transformation after major cell injuries. This hypothesis would explain the decreased risk of both solid tumours and secondary cancers.
 ...
PMID:Pattern of malignant disorders in individuals with Down's syndrome. 1190 37

We describe a novel chromosomal aberration acquired in blast crisis (BC) in a patient affected by Philadelphia-positive chronic myeloid leukemia (CML). Conventional cytogenetic studies at onset showed a classic t(9;22)(q34;q11.2) in all bone marrow cells, confirmed by fluorescence in situ hybridization and reverse transcription-polymerase chain reaction (b3a2) analysis. In BC, the malignant clone developed a new additional cytogenetic abnormality consisting of a deletion of chromosome 21. To our knowledge, this is the first case of del(21) reported in literature associated with BC CML. The use of an appropriate set of BAC/PAC clones restricted the breakpoint to an interval of approximately 100 kb. Sequence analysis did not reveal any known gene in this interval. Oncosuppressor genes distal to the breakpoint could be hypothesized to be involved in the progression of disease toward BC. Identification of new chromosome abnormalities in CML may allow further understanding of specific molecular events leading to disease evolution.
 ...
PMID:Molecular cytogenetic characterization of a novel additional chromosomal aberration in blast crisis of a Ph-positive chronic myeloid leukemia. 1203 21

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.
 ...
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.
 ...
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

The so-called Philadelphia (Ph) chromosome is present in more than 90% of chronic myeloid leukemia (CML) patients. Approximately, 5-10% of these patients show complex translocations involving a third chromosome in addition to chromosomes 9 and 22. Since at present the majority of CML cases are treated with imatinib, variant rearrangements do not exhibit specific prognostic significance. However, events of therapy resistance remain to be studied. In this study, we report a unique case of CML exhibiting an uncommon t(21;22)(p12;q11). This translocation has been characterized by fluorescence in situ hybridization (FISH) and array-proven multicolor banding (aMCB). Using specific probes for the BCR and ABL genes, results of FISH showed a three-way variant Philadelphia translocation (9;22;21)(q34;q11;p12) with a BCR/ABL fusion residing on the der(22) and the 3'BCR region translocated on the short arm of the derivative chromosome 21. In addition, the aMCB technique is significant in the detection of the breakpoints of genetic changes. The underlying mechanisms and prognostic significance of these changes are discussed.
 ...
PMID:A chronic myeloid leukemia case with a unique variant Philadelphia translocation: t(9;22;21)(q34;q11;p12). 2278 85


<< Previous 1 2