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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of 11q23-balanced translocations in acute leukemia after treatment with drugs that inhibit the function of DNA topoisomerase II (topo II) is being recognized with increasing frequency. We and others have shown that the gene at 11q23 that is involved in all of these treatment-related leukemias is MLL (also called ALL1, Htrx, and HRX). In general, the translocations in these leukemias are the same as those occurring in de novo leukemia [eg, t(9;11), t(11;19), and t(4;11)], with the treatment-related leukemias accounting for no more than 5% to 10% of any particular translocation type. We have cloned the t(11;16)(q23;p13.3) and have shown that it involves MLL and CBP (CREB binding protein). The CBP gene was recently identified as a partner gene in the t(8;16) that occurs in acute myelomonocytic leukemia (AML-M4) de novo and rarely in treatment-related acute myeloid leukemia. We have studied eight t(11;16) patients, all of whom had prior therapy with drugs targetting topo II with fluorescence in situ hybridization (FISH) using a probe for MLL and a cosmid contig covering the CBP gene. Both probes were split in all eight patients and the two derivative (der) chromosomes were each labeled with both probes. Use of an approximately 100-kb PAC located at the breakpoint of chromosome 16 from one patient revealed some variability in the breakpoint because it was on the der(16) in three patients, on the der(11) in another, and split in four others. We assume that the critical fusion gene is 5'MLL/3'CBP. Our series of patients is unusual because three of them presented with a myelodysplastic syndrome (MDS) most similar to chronic myelomonocytic leukemia (CMMoL) and one other had dyserythropoiesis; MDS is rarely seen in 11q23 translocations either de novo or with t-AML. Using FISH and these same probes to analyze the lineage of bone marrow cells from one patient with CMMoL, we showed that all the mature monocytes contained the fusion genes as did some of the granulocytes and erythroblasts; none of the lymphocytes contained the fusion gene. The function of MLL is not well understood, but many domains could target the MLL protein to particular chromatin complexes. CBP is an adapter protein that is involved in regulating transcription. It is also involved in histone acetylation, which is thought to contribute to an increased level of gene expression. The fusion gene could alter the CBP protein such that it is constitutively active; alternatively, it could modify the chromatin-association functions of MLL.
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PMID:All patients with the T(11;16)(q23;p13.3) that involves MLL and CBP have treatment-related hematologic disorders. 922 52

A case of acute myeloid leukemia (AML) M1 with bone marrow eosinophilia was characterized by cytogenetics and fluorescence in situ hybridization (FISH). A complex karyotype including a der(12)t(12;17)(p12-13;q11) and a der(16)t(16;20)(p13;p11) was found at diagnosis. FISH studies with probes for chromosome 16 and for the short arm of chromosome 12 showed even more complex rearrangements. Analysis with a panel of probes for 12p showed that D12S158 spanned the breakpoint on the der(12). Unexpectedly, FISH signals were found on the der(12) and on the der(6) at band p13, the site of juxtaposition between the short arm of chromosome 16 and chromosome 20. Moreover, both YAC 854E2, containing the MYH11 gene, and cosmid ZIT133, encompassing the MYH11 breakpoint in inv(16) and t(16;16) of AML-M4 with eosinophilia, demonstrated fluorescent signals on the normal 16, on the der(16), and on the der(12). These data clearly support a reciprocal exchange between D12S158 at 12p13.3 and the MYH11 gene at 16p13. In addition, experiments with two PAC clones for the CBFB gene at 16q22 excluded the presence of a masked inv(16). An interstitial deletion, independent from the translocation and flanked by VWF and KRAS2, was also detected on the der(12).
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PMID:Rearrangement between the MYH11 gene at 16p13 and D12S158 at 12p13 in a case of acute myeloid leukemia M1 (AML-M1). 971 91

Reciprocal translocations involving the MLL gene on chromosome band 11q23 have been observed in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). In AML, identification of MLL breakpoints is an important prognostic factor. Breakpoints are clustered in an 8 kb DNA fragment (bcr) and can be detected by Southern blotting or fluorescence in situ hybridization (FISH) analysis. Our objective in this study was to design a DNA probe set that enables optimal detection of MLL rearrangements using interphase FISH. Two PAC clones, 217A21 and 167K13, spanning the MLL gene with a minimal overlap in the bcr were isolated and labeled. Twenty-seven AML/ALL patients with cytogenetic 11q23 abnormalities, seven AML/ALL patients without 11q23 abnormalities but MLL rearrangement by Southern blotting, and eight healthy donors were analyzed by FISH. We compared this double-color FISH analysis with FISH using a YAC clone (yB22B2) and with Southern blotting. The PAC probe combination detects an MLL breakpoint in all cases with MLL rearrangement detected by Southern blotting except for cases with a partial tandem duplication detected by reverse transcriptase-polymerase chain reaction (RT-PCR). FISH using the PAC probes also detected MLL breakpoints in four cases with MLL deletions telomeric to the breakpoint that could not be detected by the single probe yB22B2. This new probe set provides a reliable and rapid assay for the diagnosis of AML and ALL patients with MLL/11q23 breakpoints.
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PMID:A DNA probe combination for improved detection of MLL/11q23 breakpoints by double-color interphase-FISH in acute leukemias. 1073 98

Rearrangements affecting chromosome band 3q21 are observed in a subgroup of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). However, little is known about the molecular consequences of such aberrations. We therefore established a PAC contig in the 3q21 breakpoint region and identified potential protein coding sequences by exon trapping. One of the exons isolated was from the human GATA-2 gene, which we showed to be transcribed from telomere to centromere. The majority of 3q21 breakpoints are located telomeric to the transcribed portion of this gene in a region that in mice appears to be necessary for proper promoter function. Results of GATA-2 expression analyses in leukemic cell lines as well as primary patient samples are compatible with the hypothesis that 3q21 aberrations contribute to leukemogenesis through deregulation of the hematopoietic transcription factor GATA-2.
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PMID:Transcription factor GATA-2 gene is located near 3q21 breakpoints in myeloid leukemia. 1087 93

Chromosome aberrations affecting band 3q21 are associated with a particularly poor prognosis in patients with acute myeloid leukaemia. To facilitate the molecular characterization of such rearrangements, we established a PAC contig covering the relevant genomic region. Using these PACs as probes in fluorescence in situ hybridization (FISH) experiments, we showed that a number of 3q21 breakpoints in patient samples map to a previously defined 'breakpoint cluster region'. Others, however, are located at varying distances centromeric of it. These results have important implications in the search for genes affected by 3q21 rearrangements.
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PMID:Mapping of leukaemia-associated breakpoints in chromosome band 3q21 using a newly established PAC contig. 1097 91

The 11p15.5 region is associated with a broad range of diseases, including childhood acute myeloid leukemia; non-small cell lung carcinoma; arthrogryposis multiplex congenita, distal type 2B; and bladder cancer. Since targets for these diseases are unknown, we have constructed a physical map consisting of BAC and PAC clones spanning the region from the HRAS1 gene to the cluster of mucin genes on 11p15.5. The contig spans approximately 500 kb and includes 13 genes (9 novel), 9 STSs (5 novel), and 1 SNP and builds upon a published physical map spanning the region from the telomere to the HRAS gene. In addition, we expand the mucin gene cluster located on 11p15.5 to include a novel mucin-like gene (MUCDHL) located less than 250 kb telomeric to MUC6. The identification of potential disease genes within an organizational and evolutionary context provides valuable clues to function and as such will benefit our understanding of this region of the genome.
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PMID:Characterization of a 500-kb contig spanning the region between c-Ha-Ras and MUC2 on chromosome 11p15.5. 1103 Nov 2

The 8p11 myeloproliferative syndrome (EMS) is associated with three translocations, t(8;13)(p11;q12), t(8;9)(p11;q33), and t(6;8)(q27;p11), that fuse unrelated genes (ZNF198, CEP110, and FOP, respectively) to the entire tyrosine kinase domain of FGFR1. In all cases thus far examined (n = 10), the t(8;13) results in an identical mRNA fusion between ZNF198 exon 17 and FGFR1 exon 9. To determine if consistent fusions are also seen in the variant translocations, we performed RT-PCR on four cases and sequenced the products. For two patients with a t(8;9), we found that CEP110 exon 15 was fused to FGFR1 exon 9. For two patients with a t(6;8), we found that FOP exon 5 (n = 1) or exon 7 (n = 1) was fused to FGFR1 exon 9. To determine if FGFR1 might be involved in other myeloid disorders with translocations of 8p, we developed a two-color FISH assay using two differentially labeled PAC clones that flank FGFR1. Disruption of this gene was indicated in a patient with a t(8;17)(p11;q25) and Ph-negative chronic myeloid leukemia in association with systemic malignant mast cell disease, a patient with acute myeloid leukemia with a t(8;11)(p11;p15), and two cases with T-cell lymphoma, myeloproliferative disorder, and marrow eosinophilia with a t(8;12)(p11;q15) and ins(12;8)(p11;p11p21), respectively. For the patient with the t(8;11), the chromosome 11 breakpoint was determined to be in the vicinity of NUP98. We conclude that 1) all mRNA fusions in EMS result in splicing to FGFR1 exon 9 but breakpoints in FOP are variable, 2) two-color FISH can identify patients with EMS, and 3) the t(8;17)(p11;q25), t(8;11)(p11;p15), t(8;12)(p11;q15), and ins(12;8)(p11;p11p21) are novel karyotypic changes that most likely involve FGFR1.
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PMID:Identification of four new translocations involving FGFR1 in myeloid disorders. 1155 Feb 83

Recently, we reported that a recurrent translocation, t(1;3)(p36;p21) is closely associated with prior chemotherapy including alkylating agents, assessing eight patients with various hematologic malignancies (Genes, Chromosomes and Cancer 34:186-192), 2002). Furthermore, we delineated the 1p36 breakpoint in two patients lying between RP11-BAC47P3 and RP5-PAC963K15 at 1p36.3 with a small deletion near the breakpoint. In one of them, we also found deletion at 3p21.3 with cosNRL9 probe, which is included in a 370-kb lung cancer homologous deletion region. However, due to scantiness of the patient materials at that time, we could not determine the precise breakpoint at 1p36 or 3p21 in any of the patients. In this report, we identified the 1p36 and 3p21 breakpoints of an AML (M3) patient who is included in the previous patient series. The patient showed t(1;3)(p36;p21) together with t(15;17) at the third relapse. With FISH using BAC/PAC probes, we determined the 1p36 breakpoint within RP11-295B1 at 1p36.2 and the 3p21 breakpoint between RP11-3B7 and RP11-901L6 at 3p21.3. There was no deletion around the two breakpoints in this patient. To the best of our knowledge, this is the first report that has identified the precise breakpoint of t(1;3)(p36;p21) translocation. It is obvious that the 1p36.2 and 3p21.3 breakpoints of this patient are different from those of the previous patients, suggesting that the genes and the molecular event is different from those of the previous patients. The patients with t(1;3)(p36;p21) should be subclassified according to the precise breakpoints or the genes involved.
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PMID:Identification of the breakpoints at 1p36.2 and 3p21.3 in an AML(M3) patient who had t(1;3)(p36.2;p21.3) at the third relapse. 1237 31

The recurrent translocation t(1;3)(p36;q21) is associated with myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML) characterized by trilineage dysplasia, especially dysmegakaryopoiesis and a poor prognosis. Recently, the two genes involved in this translocation have been identified: the MEL1 gene at 1p36.3, and the RPN1 gene at 3q21. The breakpoint in RPN1 is centromeric to the breakpoint cluster region of the inv(3) abnormality. Because the MEL1 transcript is detected only in leukemic cells with t(1;3)(p36;q21), ectopic expression of MEL1 driven by RPN1 at 3q21 is thought to contribute to the pathogenesis of t(1;3)(p36;q21) leukemia. However, the precise breakpoint in the patients has not yet been identified. With fluorescence in situ hybridization analysis by use of BAC/PAC probes, we identified the breakpoint at 1p36.3 in three MDS/AML patients with t(1;3)(p36;q21): within the first intron of the MEL1 gene (one patient) or within a 29-kb region located in the 5' region of MEL1 (two other patients). We detected several sizes of MEL1 transcript in two patients including the first patient, although we have not yet clarified whether MEL1 transcripts were different among the patients and whether a truncated MEL1 transcript was expressed in the first patient. This patient showed an unusual clinical profile, repeating progression to overt leukemia and conversion to MDS three times during the 29-month survival period, which might be related to a different molecular mechanism in this patient.
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PMID:Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. 1255 31

Fluorescence in situ hybridization analysis was carried out in five patients with acute myeloblastic leukemia of various French-American-British subtypes and with double trisomy of chromosomes 8 and 21. PML-RARA fusion was detected with appropriate molecular probes in one patient with acute promyelocytic leukemia without t(15;17). Two PAC probes covering the 5' and 3' part of the RUNX1 gene were used in the four other patients. While three copies were present in three patients, as expected from conventional karyotype analysis, only two hybridization signals were present in the fifth patient. This was due to the apparent loss of the 3' part of RUNX1. Since chromosome number abnormalities may be associated with submicroscopic gene rearrangements, it should be important to search for them for a better understanding of mechanisms of leukemogenesis, and to understand the prognostic heterogeneity in leukemic patients with aneusomies without apparent chromosome structure rearrangements.
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PMID:Double trisomy 8 and 21 in acute myelocytic leukemias, one with rearrangement of the RUNX1 gene. 1269 96


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