1/31. Alu and translisin recognition site sequences flanking translocation sites in a novel type of chimeric bcr-abl transcript suggest a possible general mechanism for bcr-abl breakpoints.BACKGROUND AND OBJECTIVE: We further characterized a novel type of chimeric BCR-ABL mRNA transcript detected in a patient with philadelphia chromosome positive (Ph ) chronic myeloid leukemia (CML). DESIGN AND methods: We used reverse-transcription polymerase chain reaction (RT-PCR) and sequence analysis of the fusion region of the amplified cDNA fragment. Western analysis was performed on total protein. RESULTS: Part of exon e8 of the BCR gene was joined to an intronic sequence of ABL intron Ib spliced on exon a2 of the ABL gene, giving rise to an in-frame e8-int-a2 BCR-ABL transcript. Only part of exon 8 of the BCR gene (e8) (intra-exonic break) was retained. The consequent BCR-int-ABL transcript was translated into a BCR-ABL protein of 1804 amino acid residues with a molecular mass of 197.5 kilodaltons (kDa) called p200 BCR-ABL. The 3' part of bcr exon 8 recombined within or alongside alu elements at the additional sites. Sequence motifs similar to consensus binding sites of the lymphoid-associated TRAX and translisin proteins were present on both participating strands at 22q11 and 9q34 recombination sites, respectively. No differences in clinical or laboratory findings at diagnosis were found between this patient and CML patients with bcr-abl fusion. INTERPRETATION AND CONCLUSIONS: The presence of Alu sequences and of the translisin binding motif on both sides of the breaks in this novel translocation suggests a possible general mechanism of molecular recombination in CML patients.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
2/31. Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21).The reciprocal translocation t(1;3)(p36;q21) is associated with myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) characterized by trilineage dysplasia, in particular dysmegakaryocytopoiesis, and a poor prognosis. As yet no molecular genetic analyses of the t(1;3) have been reported. In four patients with t(1;3), all of whom had AML-M4, which evolved from MDS, the breakpoints at 3q21 clustered within a 60-kb region centromeric to the breakpoint of the inv(3)(q21q26), whereas the breakpoints at 1p36 clustered within a 90-kb region at 1p36.3. The presence of novel clusters in both the 3q21 and 1p36 breakpoints (BCRs) suggests a common, underlying molecular mechanism for the development of t(1;3)-positive MDS/AML. The Ribophorin I (RPN1) gene close to the BCR at 3q21 was highly expressed without gross structural changes, whereas the GR6 gene located within the BCR at 3q21 was not expressed. No other highly expressed genes were isolated in a 150-kb region at 3q21. Thus, it is likely that a gene at 1p36.3 is activated by the translocation of the 3q21 region or a gene important for transformation lies on 3q21, outside the 150-kb region. Further characterization of the BCRs at 1p36.3 and 3q21 should provide important insights into the molecular genetic mechanisms involved in the genesis of t(1;3)-positive MDS/AML. Genes chromosomes Cancer 27:229-238, 2000.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
3/31. Concurrent translocations of MLL and CBFA2 (AML1) genes with new partner breakpoints in a child with secondary myelodysplastic syndrome after treatment of acute lymphoblastic leukemia.The MLL gene at 11q23 is frequently disrupted by chromosomal translocations in de novo acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), and in secondary leukemia induced by treatment with inhibitors of topoisomerase II, including the epipodophylotoxins. The CBFA2 gene at 21q22 is also frequently disrupted in de novo ALL and AML and less commonly in secondary AML. Rearrangements of MLL and CBFA2 have been described in de novo and secondary myelodysplastic syndrome (MDS). There have been no previous descriptions of coexisting abnormalities of MLL and CBFA2 in cases of MDS or acute leukemia. We describe a patient who developed secondary MDS after chemotherapy for hyperdiploid ALL. At the time of conversion to MDS, the patient had 46 chromosomes, with an 11q23/MLL translocation involving a new partner breakpoint at 2p23 and a 21q22/CBFA2 translocation involving a new partner breakpoint at 6p22. This report is the first to describe new partner breakpoints at 2p23 and 6p22 for MLL and CBFA2 genes, respectively, and concurrent rearrangements of these genes in a patient with secondary MDS.- - - - - - - - - - ranking = 8keywords = leukemia (Clic here for more details about this article) |
4/31. NUP98 gene rearrangements and the clonal evolution of chronic myelogenous leukemia.The role of the BCR-ABL fusion gene in the pathogenesis of the chronic phase of chronic myelogenous leukemia (CML) has been well established. Several additional genetic changes have been reported to occur, at varying frequencies, during disease progression to "accelerated" and "blast crisis" phases. The NUP98 gene localized to chromosome band 11p15 has been found at the breakpoints of several distinct chromosomal translocations in patients with both de novo and therapy-related myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). Using combined cytogenetic and molecular analyses, we have found rearrangements of the NUP98 gene in the leukemic cells of two patients with philadelphia chromosome-positive CML, during disease evolution. As expected, analysis of the t(7;11)(p15;p15) from one of the patients showed an in-frame NUP98-HOXA9 fusion. The fusion points were similar to previously reported NUP98-HOXA9 fusion points from patients with MDS/AML. Our results indicate that the NUP98 gene is an additional, albeit infrequent, genetic target during clonal evolution of CML.- - - - - - - - - - ranking = 6keywords = leukemia (Clic here for more details about this article) |
5/31. Acute myeloid leukemia with inv(8)(p11q13).A patient with acute monoblastic leukemia (AML M5a) and the pericentric inversion inv(8)(p11q13) as well as additional chromosome abnormalities in her bone marrow cells is described. This is the fourth known case of inv(8)(p11q13)-positive acute leukemia, and the second such case in which gain of 1q material occurred during clonal evolution. All patients with acute leukemia and inv(8)(p11q13) have been females, most have been young, and there has been a tendency for the disease to run an aggressive course. Both hematologically and cytogenetically, therefore, inv(8)(p11q13)-positive leukemia may be viewed as a variant of AML with t(8;16)(p11;p13). This similarity is also apparent at the molecular genetic level, in-as-much as the MOZ gene in 8p11 is rearranged in both the translocation and the inversion; in t(8;16)-positive leukemia, a MOZ-CBP chimeric gene is generated, whereas inv(8) has been shown to generate a MOZ-TIF2 fusion gene. Southern blot analysis of the present case after MOZ0.8 hybridization of Bam HI digested dna gave an 11 kb aberrant band in addition to the germline band, corresponding to a breakpoint immediately upstream of the 4 kb long MOZ exon that begins at position 3746. Also previously investigated inv(8)-positive leukemias have shown breaks in this intron indicating that it contains sequence motifs predisposing to illegitimate recombination.- - - - - - - - - - ranking = 10keywords = leukemia (Clic here for more details about this article) |
6/31. Insertion (22;9)(q11;q34q21) in a patient with chronic myeloid leukemia characterized by fluorescence in situ hybridization.An unusual cytogenetic rearrangement, described as ins(22;9)(q11;q34q21), was detected in a 49-year-old male patient diagnosed with chronic myeloid leukemia (CML). reverse transcriptase polymerase chain reaction (RT-PCR) revealed a b3a2 fusion transcript. In order to confirm the cytogenetic findings and fully characterize the inverted insertion, we performed fluorescence in situ hybridization (FISH) assays using locus-specific and whole chromosome painting probes. Our FISH analysis showed the presence of the BCR/ABL fusion gene, verified the insertion and determined that the breakpoint on chromosome 22 where the insertion took place was located proximal to the BCR gene and distal to the TUPLE1 gene on 22q11.- - - - - - - - - - ranking = 5keywords = leukemia (Clic here for more details about this article) |
7/31. Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23).The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with dna topoisomerase ii inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.- - - - - - - - - - ranking = 7keywords = leukemia (Clic here for more details about this article) |
8/31. Fusion of the BCR and the fibroblast growth factor receptor-1 (FGFR1) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: the first fusion gene involving BCR but not ABL.Constitutive activation of tyrosine kinases as a consequence of chromosomal translocations, forming fusion genes, plays an important role in the development of hematologic malignancies, in particular, myeloproliferative syndromes (MPSs). In this respect, the t(9;22)(q34;q11) that results in the BCR/ABL fusion gene in chronic myeloid leukemia is one of the best-studied examples. The fibroblast growth factor receptor 1 (FGFR1) gene at 8p11 encodes a transmembrane receptor tyrosine kinase and is similarly activated by chromosomal translocations, in which three alternative genes-ZNF198 at 13q12, CEP110 at 9q34, and FOP at 6q27-become fused to the tyrosine kinase domain of FGFR1. These 8p11-translocations are associated with characteristic morphologic and clinical features, referred to as "8p11 MPS." In this study, we report the isolation and characterization of a novel fusion gene in a hematologic malignancy with a t(8;22)(p11;q11) and features suggestive of 8p11 MPS. We show that the breakpoints in the t(8;22) occur within introns 4 and 8 of the BCR and FGFR1 genes, respectively. On the mRNA level, the t(8;22) results in the fusion of BCR exons 1-4 in-frame with the tyrosine kinase domain of FGFR1 as well as in the expression of a reciprocal FGFR1/BCR chimeric transcript. By analogy with data obtained from previously characterized fusion genes involving FGFR1 and BCR/ABL, it is likely that the oligomerization domain contributed by BCR is critical and that its dimerizing properties lead to aberrant FGFR1 signaling and neoplastic transformation.- - - - - - - - - - ranking = 1keywords = leukemia (Clic here for more details about this article) |
9/31. Evidence for position effects as a variant ETV6-mediated leukemogenic mechanism in myeloid leukemias with a t(4;12)(q11-q12;p13) or t(5;12)(q31;p13).The ETV6 gene (first identified as TEL) is a frequent target of chromosomal translocations in both myeloid and lymphoid leukemias. At present, more than 40 distinct translocations have been cytogenetically described, of which 13 have now also been characterized at the molecular level. These studies revealed the generation of in-frame fusion genes between different domains of ETV6 and partner genes encoding either kinases or transcription factors. However, in a number of cases-including a t(6;12)(q23;p13), the recurrent t(5;12)(q31;p13), and some cases of the t(4;12)(q11-q12;p13) described in this work-functionally significant fusions could not be identified, raising the question as to what leukemogenic mechanism is implicated in these cases. To investigate this, we have evaluated the genomic regions at 4q11-q12 and 5q31, telomeric to the breakpoints of the t(4;12)(q11-q12;p13) and t(5;12)(q31;p13). The homeobox gene GSH2 at 4q11-q12 and the IL-3/CSF2 locus at 5q31 were found to be located close to the respective breakpoints. In addition, GSH2 and IL-3 were found to be ectopically expressed in the leukemic cells, suggesting that expression of GSH2 and IL-3 was deregulated by the translocation. Our results indicate that, besides the generation of fusion transcripts, deregulation of the expression of oncogenes could be a variant leukemogenic mechanism for translocations involving the 5' end of ETV6, especially for those translocations lacking functionally significant fusion transcripts.- - - - - - - - - - ranking = 5keywords = leukemia (Clic here for more details about this article) |
10/31. t(1;3)(p36;p21) is a recurring therapy-related translocation.Chromosome bands 1p36 and 3p21 are known to be recurring breakpoints in therapy-related (t-) leukemia. We identified a recurring translocation, t(1;3)(p36;p21), in eight patients with various hematologic malignancies: three patients with ALL, one with chronic myelogenous leukemia (CML) in accelerated phase (AP), two with MDS, and two with AML(M3). Five of the eight patients had a history of chemotherapy, including alkylating agents in three, before the translocation was detected. In two of these five patients, the t(1;3)(p36;p21) emerged only at relapse or in the accelerated phase of CML. The karyotypes of the patients were complex, including -7 and structural abnormalities of 5q, 6q, 7q, 9p, and 11q23. survival time varied among patients (25 days to more than 16 years). Using FISH with 13 1p35-36 cosmid probes (tel-FB12-CA5-G7-FD2-CB1-ED8-FD9-G32-AE3-G50-AD8-GG4-G43-cen), we delineated the 1p36 breakpoint in two patients with MDS and ALL as lying between FB12 and FD2 (between BAC47P3 and PAC963K15), with a small deletion near the breakpoint in both cases. In the patient with MDS, there was also a deletion at 3p21.3, as detected with the cosmid probe cosNRL9. The results of the present study suggest that t(1;3)(p36;p21) in hematologic diseases is associated with prior exposure to mutagens, including alkylating agents.- - - - - - - - - - ranking = 2keywords = leukemia (Clic here for more details about this article) |
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