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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Translocations of the MLL gene at chromosome band 11q23 are the most common cytogenetic alterations in de novo leukemia in infants and in leukemia related to chemotherapy with DNA topoisomerase II inhibitors. Experiments on knock-in mice suggest that additional mutational events may by required for full leukemogenesis. Therefore, we used single-strand conformation polymorphism analysis and an allele-specific restriction enzyme assay to investigate the frequency of KRAS and NRAS mutations in 32 pediatric leukemias with translocation of the MLL gene. Of 25 de novo cases, 13 were acute lymphoblastic leukemia (ALL), 10 were acute myeloid leukemia (AML), and 2 were biphenotypic. Three secondary leukemias were AML, 1 was biphenotypic, 1 was ALL, and 2 were diagnosed as myelodysplasia. The frequency of RAS mutations was 2 of 10 in de novo AML. Both mutations occurred in infant monoblastic variants. RAS mutations were otherwise absent in this series. This is the first report of congenital leukemias where translocation of the MLL gene and RAS mutation coexist. The frequency of RAS mutations in de novo AMLs with MLL gene translocations is similar to that in other forms of AML, but RAS mutations play a limited role in lymphoid and treatment-related leukemias with similar translocations.
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PMID:RAS mutations in pediatric leukemias with MLL gene rearrangements. 952 5

11q23 translocations (t(11q23)) are recurring cytogenetic abnormalities in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia, involving the same gene, ALL1 (or MLL). Mixed lineage antigen expression has been reported in these leukemias, but its frequency and clinical significance are unknown. We immunophenotyped leukemia cells from 19 adult de novo AML patients with t(11q23) by multiparameter flow cytometry. Translocations included t(6;11)(q27;q23), t(9;11)(p22;q23), t(9;11;19)(p22;q23;q13.3), t(2;11)(11;17)(q37;q11q23;q11), t(11;17)(q23;q25), t(11;19)(q23;p13.1), t(11;19)(q23;p13.3) and t(11;22)(q23;q11). FAB types were M4 and M5. The committed stem cell and myeloid antigens HLADr, CD4dim, CD11b, CD13, CD15, CD32, CD33, CD38 and CD64 were each expressed in 80-100% of cases, and the early stem cell and lymphoid antigens CD34, CD56, CD3, CD2 and CD7 in 42, 39, 16, 5 and 5%, respectively. Antigen expression frequencies did not differ from those in 443 adequately karyotyped M4 and M5 cases without t(11q23). Fifteen patients (79%) attained complete remission (CR); median CR duration and survival were 10.0 and 15.1 months. CR duration and survival did not correlate with antigen expression. In particular, patients with t(9;11) survived longer than those with other t(11q23) (median not reached vs 7.6 months; P = 0.048), but antigen expression did not differ in the two groups. Thus frequencies of lymphoid antigen expression are similar in AML with t(11q23) and in other FAB M4 and M5 cases, treatment outcome does not differ in t(11q23) cases with and without lymphoid antigen expression, and better outcome of patients with t(9;11) compared to other t(11q23) does not correlate with differences in antigen expression. Mixed lineage antigen expression is not a distinctive feature of AML with t(11q23).
Leukemia 1998 Mar
PMID:Acute myeloid leukemia with 11q23 translocations: myelomonocytic immunophenotype by multiparameter flow cytometry. 952 25

The MLL gene is frequently rearranged in acute human leukemia of both the myeloid and lymphoid lineages. Using a sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) assay, we identified several abnormally spliced transcripts in which MLL exons were joined in an order different from the genomic orientation (scrambled exons). Mis-splicing of MLL was present in both normal and malignant tissues. Although the majority of these scrambled transcripts were joined accurately at consensus splice sites, there were several examples in which the junctions of exons spliced in aberrant order were at non-consensus sites. A number of features differentiate mis-splicing of MLL from the previously described cases of scrambled exons and circular RNAs. Some scrambled transcripts appear to be present in the polyadenylated fraction of RNA. No correlation of exon scrambling with exon skipping was found, and there was no particular tendency for the exons involved to be near large introns. Our data show that splicing of MLL is extremely complex. The presence of scrambled transcripts in both normal and leukemic cells, indistinguishable from transcripts resulting from genomic MLL rearrangements, precludes the use of nested RT-PCR as a screening method for detection of tandem duplication of tandem duplication of MLL.
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PMID:Exon scrambling of MLL transcripts occur commonly and mimic partial genomic duplication of the gene. 954 Jul 77

A patient previously diagnosed with chronic neutrophilic leukemia (CNL) was studied using fluorescent in situ hybridization (FISH) to determine clonality of neutrophils. By cytogenetic studies the patient's blood and bone marrow had an 11q14 deletion and were negative for the Philadelphia (Ph) chromosome. FISH was performed on peripheral blood smears using probes for the bcr/abl translocation and a probe for 11q23 (MLL). The patient's white blood cells were negative for the bcr/abl translocation; neutrophils and eosinophils, but not lymphocytes, were monosomic for the 11q23 probe indicating a clonal population within the neutrophil population.
Leukemia 1998 Apr
PMID:Demonstration of clonality in neutrophils using FISH in a case of chronic neutrophilic leukemia. 955 23

Thirty patients representing 5.5% of those collected by the 11q23 workshop had a t(6;11)(q27;q23). They included 27cases of acute myeloid leukemia (AML) (M1, three cases; M2, two cases; M4, nine cases; M4/M5, one case; M5, 12 cases) of age range 3-72 years and three cases of acute lymphoblastic leukemia (ALL) (B-lineage ALL, two cases; T-ALL, one case) of age range 0.5-13 years. In 20 cases the t(6;11) was the sole abnormality. In 10 cases the recurrent additional abnormalities were extra copies of chromosomes 8, 19, 21, or the der(6). Translocation t(6;11) was identified by cytogenetics alone in 13 cases. In three cases it was confirmed by fluorescence in situ hybridization (FISH) using whole chromosome paints (wcps) 6 and 11. In a further 14 cases involvement of MLL was demonstrated by FISH, by reverse transcriptase polymerase chain reaction (RT-PCR), by Southern blotting (SB) or by a combination of these methods. One case had a direct insertion of 11 into 6-dir ins(6;11)(q27;q13q23). Molecular investigations showed that one case had a 3' deletion of MLL. The median overall survival for the patients was 12 months, indicating a poor prognosis for patients with a t(6;11) translocation.
Leukemia 1998 May
PMID:The t(6;11)(q27;q23) translocation in acute leukemia: a laboratory and clinical study of 30 cases. EU Concerted Action 11q23 Workshop participants. 959 82

The MLL gene located at 11q23 has been described as a 'promiscuous' gene due its involvement with a large number of genetic partners. The EU Concerted Action Workshop on 11q23 provided 550 cases for study of which 82 showed abnormalities which did not involve the established translocations or deletion of 11q23. In these 'other' cases, which included inversions and duplications, 11q23 was found to be involved with 25 chromosome partners of which 10 had not been previously reported. These were 1q31, 4p11, 6q13, 8q21, 10q22, 10q25, 11q11, 11q21, 13q34 and 18q23. This study demonstrated the value of the Workshop, in confirming the diversity of chromosomal partner sites involved with 11q23 and in the identification of new partners.
Leukemia 1998 May
PMID:Ten novel 11q23 chromosomal partner sites. European 11q23 Workshop participants. 1008 43

Balanced translocations of 11q23 are associated with specific clinical features and a poor outcome, but the relevance of deletions involving 11q23 is not clear. Fifty-seven patients with this deletion were collected by the Workshop, 30 had terminal and 27 had interstitial deletions. Twenty-seven patients had acute lymphoblastic leukemia (ALL), 16 had acute myeloid leukemia (AML), one had acute biphenotypic leukemia, one had acute undifferentiated leukemia and 12 had myelodysplastic syndrome (MDS). ALL patients had a median age of 7 years, median white blood cell count (WBC) of 15 x 10(9)/l, and 10/24 had common ALL. AML patients had a median age of 23 years, a median WBC of 49 x 10(9)/l, and 9/16 had M4 or M5. MDS patients were all adult, median age of 69 years, median WBC of 3 x 10(9)/l, and 7/12 had refractory anemia. The clinical outcome depended on diagnosis: children with ALL had a better prognosis (4/16 relapsed, one died) than AML patients; all adults and children with AML and 5/12 MDS patients died. Fluorescence in situ hybridization (FISH) identified 3 del(11q23) as translocations or insertions. Molecular studies revealed a MLL rearrangement in 8/10 patients. Because the involvement of MLL might be of prognostic relevance, identification of a del(11q23) should be an indication for FISH and molecular studies.
Leukemia 1998 May
PMID:Hematological malignancies with a deletion of 11q23: cytogenetic and clinical aspects. European 11q23 Workshop participants. 959 87

Cytogenetic and molecular analyses of 11q23/MLL positive hematologic malignancies show that der(11) encodes the critical 5'MLL/3'partner gene transcript. The role of der(non-11) bearing the 5'partner/3'MLL fusion is less certain. The cytogenetic evidence for der(11) as the critical partner was investigated. Among 1680 cases (550 workshop and 1130 published) 31 cases displayed a three-way (29 cases) or four-way (two cases) translocation and 26 had only one of the derivatives. The critical junction created by t(11;n)(q23;n) was seen in all six cases of t(1;11)(q21;q23), in both cases of t(6;11)(q27;q23), in all six cases of t(11;19)(q23;p13), in nine of 11 cases with t(4;11)(q21;q23) and in 17 of 20 cases with t(9;11)(p21-22;q23). These findings support the evidence for der(11) encoding the critical leukemogenic fusion transcript. In contrast, additional change involving duplication of one of the derivatives resulted in duplication only of the non-critical der(non-11) as follows: +der(4)t(4;11)(q21;q23) [9/553], +der(6)t(6;11)(q27;q23) [3/61], +der(9)t(9;11)(p21-22;q23) [5/291] and +der(19)t(11;19)(q23;p13) [6/164]. A literature search of other neoplastic disorders showed that either derivative may be duplicated. Duplication of the non-critical derivative is the norm in AML patients with t(8;21)(q22;q22) or t(15;17)(q22;q12-21). We suggest that the genomic imbalance, rather than over-expression of the noncritical 5'partner/3'MLL, is likely to be the important outcome.
Leukemia 1998 May
PMID:Derivative chromosomes of 11q23-translocations in hematologic malignancies. European 11q23 Workshop participants. 959 88

We examined the MLL genomic translocation breakpoint in acute myeloid leukemia of infant twins. Southern blot analysis in both cases showed two identical MLL gene rearrangements indicating chromosomal translocation. The rearrangements were detectable in the second twin before signs of clinical disease and the intensity relative to the normal fragment indicated that the translocation was not constitutional. Fluorescence in situ hybridization with an MLL-specific probe and karyotype analyses suggested t(11;22)(q23;q11. 2) disrupting MLL. Known 5' sequence from MLL but unknown 3' sequence from chromosome band 22q11.2 formed the breakpoint junction on the der(11) chromosome. We used panhandle variant PCR to clone the translocation breakpoint. By ligating a single-stranded oligonucleotide that was homologous to known 5' MLL genomic sequence to the 5' ends of BamHI-digested DNA through a bridging oligonucleotide, we formed the stem-loop template for panhandle variant PCR which yielded products of 3.9 kb. The MLL genomic breakpoint was in intron 7. The sequence of the partner DNA from band 22q11.2 was identical to the hCDCrel (human cell division cycle related) gene that maps to the region commonly deleted in DiGeorge and velocardiofacial syndromes. Both MLL and hCDCrel contained homologous CT, TTTGTG, and GAA sequences within a few base pairs of their respective breakpoints, which may have been important in uniting these two genes by translocation. Reverse transcriptase-PCR amplified an in-frame fusion of MLL exon 7 to hCDCrel exon 3, indicating that an MLL-hCDCrel chimeric mRNA had been transcribed. Panhandle variant PCR is a powerful strategy for cloning translocation breakpoints where the partner gene is undetermined. This application of the method identified a region of chromosome band 22q11.2 involved in both leukemia and a constitutional disorder.
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PMID:t(11;22)(q23;q11.2) In acute myeloid leukemia of infant twins fuses MLL with hCDCrel, a cell division cycle gene in the genomic region of deletion in DiGeorge and velocardiofacial syndromes. 960 Sep 80

Segmental jumping translocations are chromosomal abnormalities in treatment-related leukemias characterized by multiple copies of the ABL and/or MLL oncogenes dispersed throughout the genome and extrachromosomally. Because gene amplification potential accompanies loss of wild-type p53, we examined the p53 gene in a case of treatment-related acute myeloid leukemia (t-AML) with MLL segmental jumping translocation. The child was diagnosed with ganglioneuroma and embryonal rhabdomyosarcoma (ERMS) at 2 years of age. Therapy for ERMS included alkylating agents, DNA topoisomerase I and DNA topoisomerase II inhibitors, and local radiation. t-AML was diagnosed at 4 years of age. The complex karyotype of the t-AML showed structural and numerical abnormalities. Fluorescence in situ hybridization analysis showed multiple copies of the MLL gene, consistent with segmental jumping translocation. A genomic region including CD3, MLL, and a segment of band 11q24 was unrearranged and amplified by Southern blot analysis. There was no family history of a cancer predisposing syndrome, but single-strand conformation polymorphism (SSCP) analysis detected identical band shifts in the leukemia, ganglioneuroma, ERMS, and normal tissues, consistent with a germline p53 mutation, and there was loss of heterozygosity in the ERMS and the t-AML. Sequencing showed a CGA-->TGA nonsense mutation at codon 306 in exon 8. The results of this analysis indicate that loss of wild-type p53 may be associated with genomic instability after DNA-damaging chemotherapy and radiation, manifest as a complex karyotype and gene amplification in some cases of t-AML.
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PMID:Association of germline p53 mutation with MLL segmental jumping translocation in treatment-related leukemia. 961 38


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