Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q8NB91 (FAB)
 3,573 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Partial tandem duplications of the MLL gene have been associated with trisomy 11 in acute myeloid leukemia (AML) and recently, have also been reported for karyotypically normal AML. In order to test the incidence and prognostic importance of this molecular marker, we have analyzed eight cases of AML with trisomy 11 and 387 unselected consecutive cases with AML for partial duplications of the MLL gene. Patients with normal karyotypes and those with various chromosome aberrations were included. De novo as well as secondary leukemias including all FAB subtypes were analyzed. Performing a one-step RT-PCR with 35 cycles using an exon 9 forward primer and an exon 3 reverse primer partial tandem duplications of the MLL gene were demonstrated in 3/8 (37.5%) patients with trisomy 11. In addition, 13/387 (3.4%) of unselected cases revealed a tandem duplication. Ten of these 13 cases were cytogenetically normal, the other three cases had < or =2 additional chromosomal alterations. Sequencing of the RT-PCR products of all 16 positive cases revealed fusions of MLL exon 9/exon 3 (e9/e3) (six cases), e10/e3 (three cases), e11/e3 (four cases) or combinations of differentially spliced e10/e3 and e11/e3 (three cases) transcripts. The duplications were confirmed by genomic long range PCR and Southern blot hybridization. Twelve cases with the MLL duplication were de novo myeloid leukemia, one was a secondary AML after MDS, three were therapy-related AML (t-AML). Of the 16 MLL-duplication positive cases, seven were classified as FAB M2, two as M1, five as M4, one as M0, one as M5b. The mean age was 62.3 years for patients with MLL duplication vs 50.3 years for the control group. Of 15 adult patients, 12 received treatment. Of these, three were nonresponders, five had early relapse (< or =6 months), four relapsed between 7 and 12 months. Median survival and relapse-free interval of the MLL duplication positive group was significantly worse than those of an age-matched karyotypically normal control group. In conclusion, MLL tandem duplications (1) are less common than previously reported; (2) are preferentially observed in AML with normal karyotypes, but can also be found in the presence of chromosome alterations; (3) are not strongly associated with an FAB subtype; (4) were not observed with the prognostically favorable t(8;21), inv(16), and t(15;17), other recurrent translocations, or in complex karyotypes; and (5) identifies a subgroup of patients with an unfavorable prognosis.
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PMID:Screening for MLL tandem duplication in 387 unselected patients with AML identify a prognostically unfavorable subset of AML. 1080 9

Translocations involving the MLL gene on chromosome 11q23 occur in 5-10% of human leukemias, and involve fusion with more than 30 different partner genes. The MLL-AF10 fusion produced by the t(10;11)(p12;q23) or ins(10;11)(p12;q23q13) occurs in a small percentage of acute leukemias, most commonly acute myelogenous leukemia (AML) of the M5 FAB subtype. We report two cases of AML (M5a and M0) and one case of acute lymphoblastic leukemia containing MLL-AF10 fusion. Each case had varied clinical characteristics, despite expressing similar MLL-AF10 fusion transcripts. Including the three cases described in this report, we identified a total of 38 cases of leukemia with MLL-AF10 fusion. Approximately one-third of these are not M5 AML. Taken together, these findings emphasize that while the sentinel molecular event may be identical in a disease, the clinical presentation and outcome can vary widely.
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PMID:Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion. 1118 95

Therapy related acute myelogenous leukemia in a 55-year-old Japanese woman is described. She had been treated for a diagnosis of non-Hodgkin's lymphoma 2 years before the onset of the secondary leukemia. She was diagnosed as AML (FAB: M2) with monosomy 7, and successfully treated by an intensive combination chemotherapy followed by an autologous peripheral blood stem cell transplantation. The disease relapsed shortly after the treatment, and the karyotype analysis revealed a complex abnormality accompanied with t(9;11)(p22;q23), however, monosomy 7 was absent. Southern blotting analysis was performed, and MLL rearrangement was evident in both the bone marrow samples obtained at that time and the cryopreserved marrow cells obtained at the onset of the disease. The bone marrow sample stored in a Carnoy solution at the onset was further analyzed, and three karyotype panels showing 45,XX, -7, t(9;11)(p22;q23) were found. Like this situation, a masked MLL rearrangement may have existed in some cases with hematopoietic malignancies, and appear to be disclosed in the clinical course.
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PMID:Masked MLL gene rearrangement was disclosed in the clinical course and sequential development of chromosome abnormality in a patient with therapy related acute myelogenous leukemia. 1253 82

We have shown that the CBL gene at 11q23.3, telomeric to MLL, was fused to MLL in an adult patient with de novo acute myeloid leukemia (FAB-M1). Southern blot analysis indicated that the MLL rearrangement was involved in the chromosomal abnormality. cDNA panhandle polymerase chain reaction identified the fusion transcript, in which MLL exon 6 was fused in-frame with CBL exon 8. Long-distance PCR amplified the genomic junction region, which involved the fusion of the 3' portion of an Alu element in intron 6 of MLL with the 5' portion of an Alu element in intron 7 of CBL. The absence of extensive sequence similarity at both breakpoints of MLL and CBL indicated that the recombination was not generated through homologous recombination. MLL and CBL are located between STS markers D11S939 and D11S924. Analysis of the sequence demonstrated that the transcriptional orientation of both genes at 11q23.3 is from centromere to telomere. The results of Southern blotting in conjunction with fluorescence in situ hybridization suggest that the MLL-CBL fusion was the result of an interstitial deletion. CBL, a proto-oncogene, functions as a negative regulator of several receptor protein-tyrosine-kinase signaling pathways and as an adaptor protein in tyrosine phosphorylation-dependent signaling. CBL is the second gene at 11q23.3 found to fuse with MLL.
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PMID:Identification of CBL, a proto-oncogene at 11q23.3, as a novel MLL fusion partner in a patient with de novo acute myeloid leukemia. 1269 71

The MLL-AF9 oncogene - one of the most frequent MLL/HRX/ALL-1 rearrangements found in infantile and therapy-related leukaemias - originates from t(9;11)(p22;q23) and is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). Here, we investigated the MLL-AF9 function by means of an antisense phosphorothioate-oligodeoxyribonucleotide (MLL-AF9-PS-ODNas) using the THP-1 AML-M5 cell line carrying t(9;11). Having confirmed that MLL-AF9-PS-ODNas induces strong inhibition of THP-1 cell growth, but only a moderate increase in apoptosis, we found that MLL-AF9-PS-ODNas did not induce morpho-functional terminal differentiation or restore M-CSF-, G-CSF- or GM-CSF-induced differentiation. Moreover, THP-1 cells showed the same phenotype with/without MLL-AF9-PS-ODNas. In THP-1 cells differentiated to mature macrophage-like cells by PMA/TPA or ATRA, MLL-AF9 expression was downregulated. Thus, in the monocytic lineage, MLL-AF9 may be expressed only in early phases and can induce deregulated amplification in both nonmalignant and malignant cells, maintaining the monocytic phenotype without blocking final maturation. Our findings suggest that: (1) as well as directly promoting cell growth, MLL-AF9 may also indirectly determine phenotype; (2) other leukaemogenic mutations associated with MLL-AF9-related leukaemias should be searched for mainly in processes of resistance to apoptosis (where MLL-AF9 may play only a limited role) and differentiation blockage (where MLL-AF9 may play no role).
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PMID:MLL-AF9 oncogene expression affects cell growth but not terminal differentiation and is downregulated during monocyte-macrophage maturation in AML-M5 THP-1 cells. 1464 61

Mature B-cell acute lymphoblastic leukemia (ALL) is typically associated with the FAB-L3 morphology and rearrangement of the MYC gene, features characteristic of the leukemic phase of Burkitt's lymphoma. However, the term 'mature' has also been used to describe other rare cases of B-ALL with light-chain surface immunoglobulin expression. In contrast, infantile B-cell ALL is generally characterized by rearrangement of the MLL gene, an immature pro-B-cell phenotype, and CD10 negativity. We describe two unusual cases of infantile B-ALL with non-L3 morphology, expressing a mature B-cell phenotype (lambda sIg+, CD19+, CD10-, TdT-, and CD34-), and showing MLL rearrangement without MYC rearrangement at presentation. Both infants relapsed after months of morphologic and genetic remission. At relapse, the t(9;11) translocation was detected in both cases by spectral karyotyping. After the initial relapse, both cases followed a rapid and aggressive course. Literature search identified few similar cases, all expressed lambda surface immunoglobulin and showed MLL rearrangement (majority with the t(9;11) translocation). These cases show that B-ALL with MLL rearrangement, especially the t(9;11) translocation, can express a 'mature' B-cell phenotype and may represent a distinct subset. Identification of additional cases will further clarify the significance of MLL rearrangements in mature B-ALL.
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PMID:Mature B-cell acute lymphoblastic leukemia with t(9;11) translocation: a distinct subset of B-cell acute lymphoblastic leukemia. 1509 14

Contemporary treatment of pediatric acute myeloid leukemia (AML) requires the assignment of patients to specific risk groups. To explore whether expression profiling of leukemic blasts could accurately distinguish between the known risk groups of AML, we analyzed 130 pediatric and 20 adult AML diagnostic bone marrow or peripheral blood samples using the Affymetrix U133A microarray. Class discriminating genes were identified for each of the major prognostic subtypes of pediatric AML, including t(15;17)[PML-RARalpha], t(8;21)[AML1-ETO], inv(16) [CBFbeta-MYH11], MLL chimeric fusion genes, and cases classified as FAB-M7. When subsets of these genes were used in supervised learning algorithms, an overall classification accuracy of more than 93% was achieved. Moreover, we were able to use the expression signatures generated from the pediatric samples to accurately classify adult de novo AMLs with the same genetic lesions. The class discriminating genes also provided novel insights into the molecular pathobiology of these leukemias. Finally, using a combined pediatric data set of 130 AMLs and 137 acute lymphoblastic leukemias, we identified an expression signature for cases with MLL chimeric fusion genes irrespective of lineage. Surprisingly, AMLs containing partial tandem duplications of MLL failed to cluster with MLL chimeric fusion gene cases, suggesting a significant difference in their underlying mechanism of transformation.
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PMID:Gene expression profiling of pediatric acute myelogenous leukemia. 1522 86

Band 11q23 is known to be involved in translocations and insertions with a variety of partner chromosomes. In most cases, they lead to MLL rearrangements, resulting in a fusion with numerous genes. We report here a newborn girl who had disseminated intravascular coagulation and cutaneous tumors (granulocytic sarcomata) in whom a diagnosis of acute myeloblastic leukemia (AML) FAB-M5 was made. Conventional cytogenetics using R-banding showed 11 of the 17 metaphases observed to have a 46,XX,t(1;11)(p36.2;q23) karyotype. FISH analysis confirmed the disruption of the MLL gene. Two adult patients solely have been found to have a t(1;11)(p36;q23); however, no FISH analysis with a MLL probe was performed in both cases. Since the diagnosis was made at birth, this implies that the MLL rearrangement and the onset of the disease occurred in utero. Twenty children, including 3 newborns, have been reported to have granulocytic sarcoma associated with 11q23/MLL rearrangement. To the best of our knowledge, this is the first report of a case of congenital AML with GS arising in a patient with proven MLL rearrangement.
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PMID:Rearrangement of MLL in a patient with congenital acute monoblastic leukemia and granulocytic sarcoma associated with a t(1;11)(p36;q23) translocation. 1562 93

Band 11q23 is known to be involved in translocations and insertions with a variety of partner chromosomes. They lead to MLL rearrangement, resulting in fusion with numerous genes. We report here on a 43-year-old man presenting with asthenia and pancytopenia who was diagnosed with acute myeloblastic leukemia FAB-M5. Conventional cytogenetic techniques showed a del(11)(q21). Using a specific probe for fluorescent in situ hybridization, the MLL gene was found to be disrupted, with the 5' region being inserted into the X-chromosome (around bands q24 approximately q25), as confirmed by whole X-chromosome painting. The accumulating data on acute myeloblastic leukemia demonstrate that the 5'-MLL insertion in an X-chromosome is a rare but recurrent abnormality associated with leukemia, not only in infants, but also in adults.
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PMID:Cryptic 5' MLL gene insertion in an X-chromosome in acute myeloblastic leukemia. 1572 43

Partial tandem (PTD) and internal tandem duplications (ITD) of the MLL or FLT3 genes respectively, have been demonstrated in acute myeloid leukemia (AML). While occurrence of each of these PTD/ITD seem to confer an unfavorable prognosis, the literature contains only sparse information of the occurrence and the prognosis of simultaneous PTD/ITD of these genes. We have therefore attempted to determine the presence and its consequence in AML and with the further aim of characterizing such patients with respect to other genetic aberrations and to prototype variables in this disease. We analyzed blast cells from 250 adult patients treated at the same institution during a 15-year period for FLT3 ITD and MLL PTD and the duplications were found in 24% and 4%, respectively. The four co-duplicated cases (2%) did not differ with respect to sex, age, FAB-type, or immunophenotype, promoter methylation of p15, E-cadherin (CDH1), Estrogen receptor, MDR1, expression of apoptosis-related or multidrug resistance-related genes, though a trend toward decreased gene expression of MDR1 was observed. Two of the patients had a normal karyotypic analysis, while the remaining two showed aberrations in chromosome 11, one with trisomy 11 and the other with a der (11). The extensive molecular characterization of FLT3/MLL coduplicated patients presented here indicates that, even though they do not differ molecularly from the groups of patients with single ITDs, their prognosis and overall survival is universally poor. More patients are needed to determine whether coduplication has independent clinical implications compared to patients with single ITD/PTD.
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PMID:Delineation and molecular characterization of acute myeloid leukemia patients with coduplication of FLT3 and MLL. 1610 73


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