ABSTRACT
The inv(11)(p15q22), a rare but recurrent chromosome abnormality that creates a NUP98-DDX10 fusion gene, is associated with de novo or secondary myeloid malignancies. We report a case of acute monocytic leukemia presenting this rearrangement, studied using fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR (RT-PCR). We also review the cases of inv(11) associated with NUP98-DDX10 reported in the literature.
Subject(s)
Chromosome Inversion , Chromosomes, Human, Pair 11/genetics , DEAD-box RNA Helicases/genetics , Gene Fusion , Leukemia, Myeloid, Acute/genetics , Nuclear Pore Complex Proteins/genetics , Child , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/enzymology , Male , Molecular Sequence DataABSTRACT
The presence of acquired clonal cytogenetic abnormalities in hematopoietic cells is one of the diagnostic hallmarks of myelodysplastic syndromes (MDS). Such anomalies may help in defining prognostic groups. We analyzed eight pediatric MDS, and herein describe three new cases, one de novo and two therapy-related, presenting an unbalanced rearrangement of 1q: one of them resulted in a derivative chromosome 6 apparently identical to a previously described one. We also review all the cases of gain of 1q reported in de novo and therapy-related childhood MDS.
Subject(s)
Chromosomes, Human, Pair 1/genetics , Myelodysplastic Syndromes/genetics , Trisomy , Adolescent , Adult , Child , Child, Preschool , Chromosomes, Human, Pair 6/genetics , Fatal Outcome , Female , Humans , Karyotyping , Male , Myelodysplastic Syndromes/diagnosis , Translocation, Genetic/geneticsABSTRACT
The occurrence of MLL gene rearrangement in acute megakaryoblastic leukemia (AML-M7, acute myeloid leukemia, French-American-British type M7) is very rare and limited to pediatric age: in particular, MLL-MLLT10 fusion, previously reported as characteristic of monocytic leukemia, has been reported in only one case of pediatric megakaryoblastic leukemia. We describe the second case with this association in light of the few reported cases of AML-M7 with MLL and/or 11q23 involvement.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Leukemia, Megakaryoblastic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Child, Preschool , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Male , Myeloid-Lymphoid Leukemia Protein , Translocation, GeneticABSTRACT
The rare t(9;11)(p22;p15) translocation is associated with adult acute myeloid leukemia (AML) with immature forms. We report a novel fusion of the NUP98 and LEDGF genes in a pediatric AML with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes exhibiting the same chromosomal rearrangement. Fluorescence in situ hybridization (FISH) and reverse transcriptase-PCR (RT-PCR) studies identified the chimeric transcript product of in-frame fusion of NUP98 exon 8 to LEDGF exon 4.
Subject(s)
Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 22 , Intercellular Signaling Peptides and Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Nuclear Pore Complex Proteins/genetics , Translocation, Genetic , Artificial Gene Fusion , Child, Preschool , Chromosome Mapping , Female , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Cytogenetic studies of acute monoblastic leukemia cases presenting MLL-MLLT10 (alias MLL-AF10) fusion show a broad heterogeneity of chromosomal breakpoints. We present two new pediatric cases (French-American-British type M5) with MLL-MLLT10 fusion, which we studied with fluorescence in situ hybridization. In both we detected a paracentric inversion of the 11q region that translocated onto chromosome 10p12; one case displayed a variant complex pattern. We review the cytogenetic molecular data concerning the proximal inversion breakpoint of 11q and confirm its heterogeneity.
Subject(s)
Chromosomes, Human, Pair 11/genetics , Gene Rearrangement , Genetic Heterogeneity , Leukemia, Monocytic, Acute/genetics , Oncogene Proteins, Fusion/genetics , Chromosome Breakage , Chromosome Inversion , Chromosomes, Human, Pair 10/genetics , Humans , In Situ Hybridization, Fluorescence , Infant , Karyotyping , Myeloid-Lymphoid Leukemia Protein , Translocation, GeneticABSTRACT
PDGFRB, a transmembrane tyrosine kinase receptor for platelet-derived growth factor, is constitutively activated by gene fusion with different partners in myeloproliferative/myelodysplastic disorders with peculiar clinical characteristics. Six alternative partner genes have been described thus far. In this study, we report the molecular cloning of a novel translocation t(5;17)(q33;p11.2) in a case of juvenile myelomonocytic leukemia. The novel partner gene was identified as HCMOGT-1 using 5'-rapid amplification of cDNA ends; fluorescence in situ hybridization and reverse transcriptase-PCR analyses confirmed that the translocation resulted in PDGFRB/HCMOGT-1 fusion. We show that the breakpoint of PDGFRB occurred at the same site of all previously reported PDGFRB translocations.
Subject(s)
Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 5/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Recombinant Fusion Proteins/genetics , Translocation, Genetic , Cell Cycle Proteins , Cytoskeletal Proteins , Humans , In Situ Hybridization, Fluorescence , Infant , Male , Nuclear ProteinsABSTRACT
Human neuroblastoma (NB) tumors elaborate angiogenic peptides, and enhanced angiogenesis correlates with their aggressive behavior, metastatic spread and poor clinical outcome. Hence, inhibition of angiogenic factor production may represent a potential therapeutic target for NB treatment. There is currently little information regarding the stimuli that control NB production of angiogenic mediators. In this study, we analyzed the effects of hypoxia, a common feature of solid tumors and a major drive to tumor angiogenesis, and of PA, a tryptophan catabolite produced under inflammatory conditions and endowed with several biologic properties, on the production of the angiogenic activator VEGF by advanced-stage human NB cell lines. We demonstrate that both stimuli are potent inducers of VEGF expression and secretion. VEGF upregulation by PA involved iron chelation because iron sulfate prevented this effect whereas the iron-chelating agent DFX induced VEGF production. Conversely, the CDK inhibitor Flp completely blocked VEGF induction by hypoxia. This effect occurred as early as 3 hr after stimulation and did not require de novo protein synthesis. Moreover, Flp exerted similar inhibitory activity on VEGF induction by PA or DFX, suggesting that this compound targets an essential step in the signaling pathway that leads to VEGF expression. Our findings demonstrate that PA can modulate angiogenic factor production by tumor cells and establish the importance of Flp as an inhibitor of VEGF production by human NB.
Subject(s)
Antineoplastic Agents/pharmacology , Cell Hypoxia , Endothelial Growth Factors/biosynthesis , Flavonoids/pharmacology , Lymphokines/biosynthesis , Neuroblastoma/metabolism , Picolinic Acids/pharmacology , Piperidines/pharmacology , Deferoxamine/pharmacology , Endothelial Growth Factors/antagonists & inhibitors , Endothelial Growth Factors/genetics , Ferrous Compounds/pharmacology , Gene Expression/drug effects , Humans , Iron Chelating Agents/pharmacology , Lymphokines/antagonists & inhibitors , Lymphokines/genetics , RNA, Messenger/analysis , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth FactorsABSTRACT
Congenital, or perinatal, leukemias are rarely observed, but retrospective molecular studies seem to suggest a more frequent onset in prenatal life. Myelocytic types are common, and chromosome band 11q23 rearrangements at the MLL locus are characteristic genetic markers. The fusion of the MLL gene with one of its partners, ABI-1, has recently been described in two infant leukemia patients with monocytic involvement and good clinical outcome. We report a case of congenital monocytic leukemia with the same gene involvement and good response to chemotherapy. The blast metaphases were probed by fluorescence in situ hybridization, and t(10;11)(p11.2;q23) involving MLL and ABI-1 genes was demonstrated with the same breakpoint in ABI-1. The congenital presentation of this case suggests a possible relationship of this genetic event with in utero leukemogenesis.
