Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: KEGG:D01078 (TEL)
781 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Childhood cancer is rare comprising less than 1% of all malignancies diagnosed each year in developed countries. Leukaemia is the commonest form of cancer in children accounting for around a third of all childhood cancer, with acute lymphoblastic leukaemia (ALL) being the most prevalent. Biologically specific subtypes of ALL and acute myeloblastic leukaemia (AML), the other major morphological type of childhood leukaemia, are characterised by chromosomal changes. Whilst over 200 genes have been associated with chromosomal translocations, to date, only MLL, TEL, and AML1 have been linked with childhood leukaemia. Interestingly, there is increasing evidence to support the theory that gene rearrangements such as these may originate in utero. As with many other human diseases, both genetic and environmental factors have been implicated in the aetiology of the disease. Although much has been documented with regard to diet, smoking, alcohol consumption and recreational and prescription drug use during pregnancy, there is no consistent evidence to support a link with any of these factors and childhood leukaemia. However, findings from studies investigating prenatal and early life exposures are often based on small numbers of cases as both the type of cancer and exposure are rare. Furthermore, accurate information relating to past exposures can be difficult to obtain and is often reliant on self-reporting. To further our understanding of the aetiology of childhood leukaemia and lymphoma, there are areas which clearly warrant investigation. These include collection of parental dietary folate data combined with genetic analysis of the folate related genes, in utero exposure to DNA topoisomerase II inhibitors, and the possible effects of assisted reproduction technology on disease susceptibility.
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PMID:Causes of childhood leukaemia and lymphoma. 1531 83

In about 55% of acute myeloid leukemia (AML) cases, chromosome aberrations are detectable by cytogenetics. Close correlations between cytomorphology and cytogenetics have been reported. To determine a pattern of cytogenetic abnormalities within the French-American-British (FAB) subtypes AML M0, M1, and M2, we analyzed 48 AML M0, 179 AML M1, and 425 AML M2 and compared cytogenetic data to a cohort of 1,062 AML M3/3v, M4, M4eo, M5a/5b, M6, and M7. Cytogenetic abnormalities were significantly more frequent in AML M0 (71%) compared to M1 (49%), M2 (53%), and the total cohort (56%; P < 0.02). While +8 was the most common numeric abnormality in all FAB subtypes, +13, +14, and +11 were associated with AML M0-M2. The only recurring balanced translocation that was associated with one of these FAB subtypes was t(8;21) in M2 (12.5%) and, rarely, M1 (1.7%) (M0, 0% and M3-7, 0.09%; P=0.001). To evaluate the frequency of cytogenetically undetectable abnormalities, we performed fluorescence in situ hybridization (FISH) analyses in 273 AML M0-M2 with normal karyotype using probes for ETO, ABL, MLL, TEL, RB, P53, AML1, and BCR. In two cases we identified numerical aberrations of RB only in interphases nuclei. In seven additional cases, TEL and MLL abnormalities were found. In conclusion, t(8;21), +11, +13, and +14 are strongly associated with AML M0, M1, and M2. The FISH screening analyses identified abnormalities in an additional 3% in normal karyotypes.
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PMID:Cytogenetic profile in de novo acute myeloid leukemia with FAB subtypes M0, M1, and M2: a study based on 652 cases analyzed with morphology, cytogenetics, and fluorescence in situ hybridization. 1552 2

Major strides have been made in our understanding of the molecular basis of adult and pediatric leukemias. More than one hundred disease alleles have been identified and characterized in cell culture and murine models of leukemia. In some instances, molecularly targeted therapies have been developed based on these insights that are currently in clinical trials, such as small molecule inhibitors of FLT3. In addition, it has recently been appreciated that, as with normal hematopoiesis, there is a hierarchical organization among leukemic cells that includes a rare population of leukemic stem cells that have properties of self-renewal. Understanding the characteristics of these leukemic stem cells may provide new insights into leukemia therapies that target self-renewal pathways. In Section I, Dr. Craig Jordan reviews the data that supports the existence of a "leukemia stem cell." He provides an overview of the functional properties of leukemic stem cells, their relationship to hematopoietic stem cells, and the relevance of leukemic stem cells in other human malignancies including solid tumors. He briefly discusses what is known of the pathways that regulate properties of self-renewal. Dr. Gary Gilliland provides an overview of the genetics of adult leukemias in Section II and ongoing genome-wide strategies for discovery of new disease alleles. He describes the clinical and therapeutic implications of these findings and provides examples of bench-to-bedside translation of molecularly targeted therapies for AML, including the use of FLT3 inhibitors. In Section III, Dr. Carolyn Felix reviews recent advances in our understanding of the genetics and therapy of pediatric leukemias. She provides an overview of leukemias that are common in pediatric malignancies but rarely observed in adults, including the TEL-AML1 (ETV6-RUNX1) fusion associated with pediatric B-cell ALL, the OTT-MAL fusion associated with infant megakaryoblastic leukemia, PTPN11 mutations in juvenile myelomonocytic leukemia, and MLL fusion genes in leukemogenesis, among others.
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PMID:The molecular basis of leukemia. 1556 78

After stem cell transplantation (SCT) close follow-up of chimerism and/or clonal disease markers is essential for early treatment of graft failure or relapse. We wanted to assess the sensitivity, clinical reliability and practicability of inter-phase FISH on untreated, native smears of BM or PB for this purpose. We investigated 23 children after SCT with sex mismatch (MM) and/or clone specific markers (monosomy 7, trisomy 8, MLL rearrangement, bcr-abl, TEL-AML-1). Diagnoses were ALL (8), AML (6), MDS (2), CML (2), large cell anaplastic lymphoma (1) and SAA (4). Eighteen children were transplanted from sex-mismatched donors, seven among them had shown a clonal marker at diagnosis. The remaining five patients with sex matched donors also had a clonal marker. For FISH, we used commercial probes on fresh or stored unmanipulated smears of PB or BM. Cut-off levels for clonal markers were established on control probands without hematologic disease, for host sex on probands of the opposite sex, respectively (mean +3 SD). The presence of host cells and/or clonal markers established at diagnosis by conventional karyotyping was followed up after SCT at regular intervals by FISH. Nineteen of the 23 patients studied achieved and maintained complete continuous hematologic remission with corresponding absence of host and/or disease markers. In one of them, a fatal extramedullary relapse occurred. The associated mixed chimerism was confirmed by FISH. In all four cases with hematological relapse, the respective marker (MLL, bcr-abl, Mo 7) reappeared and was successfully monitored during DLI and repeat SCT in two as well as parallelled by simultaneous demonstration of host cells in the two sex mismatched cases among them. We demonstrate the usefulness of FISH on native smears for clinical routine follow-up of SCT patients. FISH allowed identification of cell origin in non-hematologic material (spinal fluid, pericardial effusion). Chimerism analysis in BM was slightly more sensitive than in PB. FISH was feasible on frozen stored smears as well.
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PMID:FISH analysis of native smears from bone marrow and blood for the monitoring of chimerism and clonal markers after stem cell transplantation in children. 1564 46

The aims of this study were to estimate the incidences of BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions in childhood acute lymphoblastic leukemia (ALL), to identify new abnormalities, and to demonstrate the usefulness of interphase fluorescence in situ hybridization (FISH). We performed G-banding analysis and FISH using probes for BCR/ABL, MLL, TEL/AML1 rearrangements, and p16 deletions on 65 childhood ALL patients diagnosed and uniformly treated at a single hospital. Gene rearrangements were identified in 73.8% of the patients using the combination of G-banding and FISH, while the chromosomal abnormalities were identified in 49.2% using G-banding alone. Gene rearrangements were disclosed by FISH in 24 (72.7%) of 33 patients with normal karyotype or no mitotic cell in G-banding. Among the gene rearrangements detected by FISH, the most common gene rearrangement was p16 deletion (20.3%) and the incidences of others were 14.1% for TEL/AML1, 11.3% for MLL, and 1.8% for BCR/ABL translocations. Infrequent or new aberrations such as AML1 amplification, MLL deletion, ABL deletion, and TEL/AML1 fusion with AML1 deletion were also observed. We established the rough incidences of gene rearrangements in childhood ALL, found new abnormalities and demonstrated the diagnostic capability of interphase FISH to identify cryptic chromosome aberrations.
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PMID:Molecular cytogenetic analysis of gene rearrangements in childhood acute lymphoblastic leukemia. 1571 99

Summary Interphase fluorescence in situ hybridization (iFISH) was used independently to reveal chromosomal abnormalities of prognostic importance in a large, consecutive series of children (n = 2367) with acute lymphoblastic leukaemia (ALL). The fusions, TEL/AML1 and BCR/ABL, and rearrangements of the MLL gene occurred at frequencies of 22% (n = 447/2027) (25% in B-lineage ALL), 2% (n = 43/2027) and 2% (n = 47/2016) respectively. There was considerable variation in iFISH signal patterns both between and within patient samples. The TEL/AML1 probe showed the highest incidence of variation (59%, n = 524/884), which included 38 (2%) patients with clustered, multiple copies of AML1. We were thus able to define amplification of AML1 as a new recurrent abnormality in ALL, associated with a poor prognosis. Amplification involving the ABL gene, a rare recurrent abnormality confined to T ALL patients, was identified for the first time. The use of centromeric probes revealed significant hidden high hyperdiploidy of 33% and 59%, respectively, in patients with normal (n = 21/64) or failed (n = 32/54) cytogenetic results. The iFISH contributed significantly to the high success rate of 91% (n = 2114/2323) and the remarkable abnormality detection rate of 89% (n = 1879/2114). This study highlights the importance of iFISH as a complementary tool to cytogenetics in routine screening for significant chromosomal abnormalities in ALL.
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PMID:Interphase molecular cytogenetic screening for chromosomal abnormalities of prognostic significance in childhood acute lymphoblastic leukaemia: a UK Cancer Cytogenetics Group Study. 1587 34

Aberrant expression of tumor suppressor genes WT 1, RB 1, p53, homozygous deletion of p16 gene and their relationship with expression of oncogenes BCR-ABL, TEL-AML 1, MLL-AF 4, E2A-PBX 1, SIL-TAL 1 were determined in bone marrow samples of children with de novo B-lineage (n=170) and T-lineage (n=25) acute lymphoblastic leukemia (ALL). In contrast to expression of chimeric oncogenes alterations in p16, WT 1, RB 1 and p53 expression were T/B-lineage-unrestricted. Significant association between expression of MLL-AF 4 and WT 1, E2A-PBX 1 and p53; SIL-TAL 1 and homozygous deletion of p16 has been demonstrated.
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PMID:Aberrant expression of tumor suppressor genes and their association with chimeric oncogenes in pediatric acute lymphoblastic leukemia. 1587 20

Bruton's tyrosine kinase (BTK) deficiency results in a differentiation block at the pre-B cell stage. Likewise, acute lymphoblastic leukemia cells are typically arrested at early stages of B cell development. We therefore investigated BTK function in B cell precursor leukemia cells carrying a BCR-ABL1, E2A-PBX1, MLL-AF4, TEL-AML1, or TEL-PDGFRB gene rearrangement. Although somatic mutations of the BTK gene are rare in B cell precursor leukemia cells, we identified kinase-deficient splice variants of BTK throughout all leukemia subtypes. Unlike infant leukemia cells carrying an MLL-AF4 gene rearrangement, where expression of full-length BTK was detectable in only four of eight primary cases, in leukemia cells harboring other fusion genes full-length BTK was typically coexpressed with kinase-deficient variants. As shown by overexpression experiments, kinase-deficient splice variants can act as a dominant-negative BTK in that they suppress BTK-dependent differentiation and pre-B cell receptor responsiveness of the leukemia cells. On the other hand, induced expression of full-length BTK rendered the leukemia cells particularly sensitive to apoptosis. Comparing BTK expression in surviving or preapoptotic leukemia cells after 10-Gy gamma radiation, we observed selective survival of leukemia cells that exhibit expression of dominant-negative BTK forms. These findings indicate that lack of BTK expression or expression of dominant-negative splice variants in B cell precursor leukemia cells can (i) inhibit differentiation beyond the pre-B cell stage and (ii) protect from radiation-induced apoptosis.
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PMID:Deficiency of Bruton's tyrosine kinase in B cell precursor leukemia cells. 1614 23

Cytogenetic analyses of lymphomas commonly reveal nonrandom chromosomal abnormalities, but there are relatively few reports in childhood lymphoblastic lymphoma (LL). We retrospectively reviewed G-banded karyotypic analyses performed at Arkansas Children's Hospital between 1990 and 2004. Six children (2 to 20 years old) had LL that presented as mediastinal or cervical masses and had a T-cell immunophenotype and clonal abnormalities. The cytogenetic findings in these 6 patients were as follows: 46,XX,-7,inv(9)(p11q12),der (12)t(7;12)(q11.2;p13),t(16;18)(p13.1;q21),+22 in patient 1; 47,XX,+9,del(9)(q11q22)x2 in patient 2; 72-119, XY,+X,+1,+1, inv(2) (p11q13),-3,+5,+6,+7,+10,-12,-16, -21,-21,-22,+mar in patient 3; 48,XY,+5,+20,t(7;9) (q32;q34) in patient 4; 47 approximately 48,XX,der(10)t(10;14)(q23; q11.2),+12, del(12)(p12)x2, -14,del(16)(q22q22),+?add (19)(p13.3) in patient 5; and 48 approximately 49,XY,+7,+8,t(11;19) (q23;p?13.3),+der(19)t(11;19)[cp20] in patient 6. Eleven chromosome breakpoints in 6 of our patients (7q11, 12p13, 16p13, 18q21, 9q11, 2p11, 2q13, 7q32, and 7q23) have been reported in other patients with acute lymphoblastic leukemia or LL and involved regions containing TEL, ABL, E2A, MLL, and T-cell receptor-alpha genes. A review of the cytogenetic findings of these and other cases of LL reveals that clonal aberrations are common and most frequently involve T-cell receptor gene regions. The aberrations show some features similar to those of acute lymphoblastic leukemia and are not unique to LL, thus furnishing additional evidence of the equivalence of these two diseases. The cytogenetic features of LL may be helpful in the diagnosis of pediatric lymphomas and undifferentiated neoplasms.
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PMID:Cytogenetic findings in pediatric T-lymphoblastic lymphomas: one institution's experience and a review of the literature. 1621 47

Global expression profiles of a consecutive series of 121 childhood acute leukemias (87 B lineage acute lymphoblastic leukemias, 11 T cell acute lymphoblastic leukemias, and 23 acute myeloid leukemias), six normal bone marrows, and 10 normal hematopoietic subpopulations of different lineages and maturations were ascertained by using 27K cDNA microarrays. Unsupervised analyses revealed segregation according to lineages and primary genetic changes, i.e., TCF3(E2A)/PBX1, IGH@/MYC, ETV6(TEL)/RUNX1(AML1), 11q23/MLL, and hyperdiploidy (>50 chromosomes). Supervised discriminatory analyses were used to identify differentially expressed genes correlating with lineage and primary genetic change. The gene-expression profiles of normal hematopoietic cells were also studied. By using principal component analyses (PCA), a differentiation axis was exposed, reflecting lineages and maturation stages of normal hematopoietic cells. By applying the three principal components obtained from PCA of the normal cells on the leukemic samples, similarities between malignant and normal cell lineages and maturations were investigated. Apart from showing that leukemias segregate according to lineage and genetic subtype, we provide an extensive study of the genes correlating with primary genetic changes. We also investigated the expression pattern of these genes in normal hematopoietic cells of different lineages and maturations, identifying genes preferentially expressed by the leukemic cells, suggesting an ectopic activation of a large number of genes, likely to reflect regulatory networks of pathogenetic importance that also may provide attractive targets for future directed therapies.
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PMID:Molecular signatures in childhood acute leukemia and their correlations to expression patterns in normal hematopoietic subpopulations. 1635 39


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