1/16. Translocation (4;15)(p16;q24): a novel reciprocal translocation in a patient with BCR/ABL negative myeloproliferative syndrome progressing to blastic phase.A patient with BCR/ABL negative myeloproliferative syndrome with a 46,XY,del(3)(q21), t(4;15)(p16;q24) karyotype is described. fluorescence in situ hybridization performed with chromosomes 4 and 15 painting probes confirmed a novel reciprocal (4;15) translocation. The absence of crkl tyrosine phosphorylation, no activation of the abl kinase as measured by autophosphorylation, and a normal-size abl transcript suggest an alternative mechanism for leukemogenesis to that operative in Ph positive BCR/ABL positive chronic myeloid leukemia. A number of genes potentially relevant to tumorigenesis, some involving the ras signaling pathway, map to the 4p16 and 15q24 chromosome regions.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
2/16. A group of previously not recognized cytogenetic abnormalities in myeloid hematological malignancies.We have identified a group of previously not reported chromosome abnormalities related to myeloid hematological malignancies. Cases 1 and 2 were observed to have an additional i(4)(p10) as the sole anomaly with similar clinical features of myeloid disorders; that is, acute nonlymphocytic leukemia (ANLL-M2) and myelodysplastic syndrome (MDS)-refractory anemia with an excess of blasts in transformation, respectively. fluorescence in situ hybridization studies with the use of a 4p-specific microdissection probe further confirmed the presence of an i(4)(p10) in these patients. Case 3 was diagnosed with ANLL-M1 and had an additional i(8)(p10) as the only change, also confirmed by a whole-chromosome painting procedure. In cases 4-6, deletions of 18q at breakpoints q12, q23, and q21 were identified as the sole anomaly in a myeloproliferative disorder (MPD), MPD, and MDS, respectively. X-autosome translocations other than t(X;10)(p11;p11) and t(X;11)(q13;q23) have not been reported as recurrent or primary changes in hematological disorders. In the present study, a t(X;9)(q26;q22) and t(X;5)(q13;q33) as the sole anomaly were found in cases 7 and 8, respectively. Both cases had the same diagnosis of MDS. Considering that trisomies 4 ( 4) and 8 ( 8) are common anomalies in MDS and ANLL, our findings strongly indicate that amplification of genes on 4p and 8p, but not on 4q and 8q, may play a crucial role in the pathogenesis of MDS and ANLL. In addition, genes on 18q12-23 and on Xq13-26 may be involved in the pathogenesis of myeloid disorders.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
3/16. Fusion of H4/D10S170 to the platelet-derived growth factor receptor beta in BCR-ABL-negative myeloproliferative disorders with a t(5;10)(q33;q21).We have studied a patient who presented with clinical features suggestive of chronic myeloid leukemia in accelerated phase. BCR-ABL transcripts were undetectable by reverse transcription-PCR, but a novel reciprocal translocation, t(5;10)(q33;q21.2), was seen by standard cytogenetic analysis. Chromosome band 5q33 contains the gene encoding the platelet-derived growth factor beta receptor (PDGFbetaR), the receptor tyrosine kinase that is disrupted by the t(5;7), t(5;12), and t(5;14) in myeloid disorders, resulting in the fusion of PDGFbetaR to HIP1, TEL/ETV6, and CEV14, respectively. Southern analysis with PDGFbetaR cDNA revealed novel bands in patient but not control DNA after digestion with several restriction enzymes, indicating that this gene is also targeted by the t(5;10). fluorescence in situ hybridization analysis of chromosome 5 indicated that a small inversion at 5q33 had taken place in addition to the interchromosomal translocation. The site of the chromosome 10 breakpoint fell within YAC 940e4. Because all PDGFbetaR fusions described thus far result in splicing to a common exon of this gene, we performed 5'-rapid amplification of cDNA ends PCR on patient rna. Several clones were isolated in which PDGFbetaR fused in frame to H4/D10S170, a previously described ubiquitously expressed gene that is fused to the ret protein tyrosine kinase to form the PTC-1 oncogene in approximately 20% of papillary thyroid carcinomas. The presence of H4-PDGFbetaR chimeric mRNA in the patient was confirmed by reverse transcription-PCR; reciprocal PDGFbeta1R-H4 transcripts were not detected. We conclude that t(5;10)(q33;q21.2) is a novel translocation in BCR-ABL-negative chronic myeloid leukemia and that this abnormality results in an H4-PDGFbetaR fusion gene. This finding further strengthens the association between myeloproliferative disorders and deregulated tyrosine kinases.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
4/16. Acute megakaryoblastic leukemia after transient myeloproliferative disorder with clonal karyotype evolution in a phenotypically normal neonate.We report a case of transient myeloproliferative disorder (TMD) in a neonate without features of down syndrome (DS) with clonal karyotype evolution, after apparent spontaneous resolution of TMD, but eventually progressing to acute megakaryoblastic leukemia (AMKL). The patient had petechiae, thrombocytopenia, and blastemia. trisomy 21 with a satellited y chromosome (Yqs) was found in proliferating blasts. A stimulated peripheral blood culture confirmed the constitutional origin of the Yqs, but did not reveal the presence of any trisomic 21 cell. By the age of 3 months, clonal chromosome evolution in the form of an interstitial deletion of the long-arm of chromosome 13 [del(13)(q13q31)] was detected along with trisomy 21 in unstimulated bone marrow cultures. However, remission was achieved without treatment at the age of 4 months. trisomy 21 and del(13)(q13q31) were not identified in either cytogenetics or fluorescence in situ hybridization studies at that time. The child was asymptomatic until the age of 20 months when anemia and thrombocytopenia prompted a bone marrow biopsy, revealing changes consistent with AMKL. The remission proceeded by clonal karyotype evolution in a neonate with TMD demonstrates that clonal karyotype evolution does not indicate an immediately progressive disease. However, the development of AMKL after TMD in this case illustrates the increased risk for leukemia in TMD cases, even without DS. The gradual clonal evolution of the blasts in our patient suggests that "multiple hits" oncogenesis applies to TMD progression to acute leukemia.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
5/16. Lineage-specific trisomy 21 in a neonate with resolving transient myeloproliferative syndrome.The cellular events that lead to transient myeloproliferative syndrome (TMS) in patients with trisomy 21 mosaicism confined to the hematopoietic system are poorly understood. The authors attempt to define the event that led to the development of TMS in a single patient with clonal trisomy 21. A phenotypically normal neonate with clonal trisomy 21 is described. At the time when his TMS was resolving, fluorescent in situ hybridization analysis was performed on cell populations sorted by flow cytometry to determine what cell populations contained trisomic cells. trisomy 21 was found in cells of the erythrocytic and monocytic lineages, but not in the stem cells, progenitor compartment, megakaryocytes, lymphocytes, or neutrophils. These results support the hypothesis that, in this neonate, trisomy 21 occurred in a multipotent hematopoietic progenitor, and a subsequent event led to the appearance of the blast population.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
6/16. Two new translocations involving the 11q23 region map outside the MLL locus in myeloid leukemias.BACKGROUND AND OBJECTIVES: In acute leukemias, chromosomal translocations involving the 11q23 band are frequently, but not invariably, associated with MLL gene rearrangement and their finding is associated with a poor prognosis. We observed two new translocations with a breakpoint in the 11q23 region at standard cytogenetic analysis: a previously undescribed t(3;11)(q21;q23) in a 70-year old woman with a fulminating form of AML-M1 and a new translocation t(6;11)(q15;q23) in a 61-year old man with an atypical chronic myelogenous leukemia. In these two patients, involvement of the MLL gene was analyzed by molecular cytogenetic techniques which also allowed a more precise mapping of the breakpoints. DESIGN AND methods: The MLL gene was analyzed by Southern blot and by fluorescent in situ hybridization (FISH) with a double-color MLL probe. A panel of 11q, 3q and 6q cosmid/YAC probes mapping around the breakpoints was used for breakpoint mapping. RESULTS: In both patients, FISH analysis and Southern blot showed that the MLL gene was not rearranged; in patient 1, MLL was retained on the 11q derivative, whereas in patient 2 it moved to the 6q- chromosome. In the t(3;11) we localized the chromosome 11 breakpoint at 11q23.3, in a region flanked by CP-939H3 and cos1p3, distal to the MLL locus; in the t(6;11) the break occurred at 11q21, in a region flanked by CP-819A5 and CP-829A6, proximal to the MLL locus. INTERPRETATION AND CONCLUSIONS: Our cases add two new translocations to the list of chromosomal anomalies involving the long arm of chromosome 11, and show that apparent translocation t(11q23) may involve loci and genes other than MLL. Characterizing the molecular heterogeneity of 11q23 translocations may identify some prognostic significance.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
7/16. Cloning of the t(1;5)(q23;q33) in a myeloproliferative disorder associated with eosinophilia: involvement of PDGFRB and response to imatinib.eosinophilia is common in myeloproliferative disorders (MPDs) with abnormalities of chromosome band 5q31-33, including those that present with t(1;5)(q23;q33). With the development of rational drug therapy, characterization of the molecular targets for these translocations could guide treatment and affect patient survival. We cloned the t(1;5)(q23;q33) and showed that it fuses platelet-derived growth factor receptor beta (PDGFRB) to the coiled-coil domains of a novel partner protein, myomegalin. Using two-color interphase fluorescence in situ hybridization (FISH), we also demonstrated that the eosinophils are clonal in these disorders. Imatinib mesylate has recently been shown to be efficacious in MPDs with PDGFR activation. Therefore, following our molecular studies, we were able to redirect this patient's treatment. Although she had refractory and progressive disease, once imatinib was started, complete clinical and hematologic remission, as well as major cytogenetic response, was achieved. Given the therapeutic implications, our findings stress the need to aggressively investigate the molecular basis of these diseases, with emphasis on the PDGFR family.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
8/16. NIN, a gene encoding a CEP110-like centrosomal protein, is fused to PDGFRB in a patient with a t(5;14)(q33;q24) and an imatinib-responsive myeloproliferative disorder.We describe a new PDGFRB fusion associated with a t(5;14)(q33;q24) in a patient with a longstanding chronic myeloproliferative disorder with eosinophilia. After confirmation of PDGFRB involvement and definition of the chromosome 14 breakpoint by fluorescence in situ hybridization, candidate partner genes were selected on the basis of the presence of predicted oligomerization domains believed to be an essential feature of tyrosine kinase fusion proteins. We demonstrate that the t(5;14) fuses PDGFRB to NIN, a gene encoding a centrosomal protein with CEP110-like function. After treatment with imatinib, the patient achieved hematological and cytogenetical remission, but NIN-PDGFRB mRNA remained detectable by reverse transcription-PCR.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
9/16. p53-Binding protein 1 is fused to the platelet-derived growth factor receptor beta in a patient with a t(5;15)(q33;q22) and an imatinib-responsive eosinophilic myeloproliferative disorder.We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to dna damage. The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRbeta, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.- - - - - - - - - - ranking = 2keywords = hybridization (Clic here for more details about this article) |
10/16. The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1.The 8p11 myeloproliferative syndrome (EMS) also known as stem cell leukemia-lymphoma syndrome (SCLL) is associated with translocations that disrupt FGFR1. The resultant fusion proteins are constitutively active tyrosine kinases, and different FGFR1 fusions are associated with subtly different disease phenotypes. We report here a patient with a t(8;17)(p11;q23) and an unusual myelodysplastic/myeloproliferative disease (MDS/MPD) characterized by thrombocytopenia due to markedly reduced size and numbers of megakaryocytes, with elevated numbers of monocytes, eosinophils and basophils. A novel mRNA fusion between exon 32 of the myosin XVIIIA gene (MYO18A) at chromosome band 17q11 and exon 9 of FGFR1 was identified. Partial characterization of the genomic breakpoints in combination of bubble-PCR with fluorescence in situ hybridization revealed that the t(8;17) arose from a three-way translocation with breaks at 8p11, 17q11 and 17q23. MYO18A-FGFR1 is structurally similar to other fusion tyrosine kinases and is likely to be the causative transforming lesion in this unusual MDS/MPD.- - - - - - - - - - ranking = 1keywords = hybridization (Clic here for more details about this article) |
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