Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Partial duplication of the MLL gene is a recently characterized novel genetic mechanism for leukemogenesis. A close association with trisomy 11 has been observed. A case of acute myelogenous leukemia (AML) M6 without karyotypic abnormality was found to have rearrangement of the MLL gene. Southern analysis with an MLL exon 2 probe revealed partial duplication of the MLL gene, with a duplicated MLL transcript amplified by reverse transcription polymerase chain reaction (RT = PCR). The presence of trisomy 11 was excluded by fluorescence in situ hybridization (FISH). Few cases of AML with MLL gene duplication have been reported, and they showed involvement of the M1, M2, and M4 subtypes. This case is the first reported case with an M6 phenotype, and highlights the importance of investigating for MLL gene mutations in all subtypes of AML, as they may carry prognostic significance.
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PMID:Partial duplication of the MLL gene in acute myelogenous leukemia without karyotypic aberration. 924 13

A 20-year-old Japanese man was referred because of severe pancytopenia with 14% of abnormal blasts in hypocellular bone marrow. After treatment by granulocyte colony-stimulating factor (G-CSF) and transfusions of red blood cells, spontaneous remission was subsequently achieved. After 3 months' remission, however, the patient developed AML characterized by the abnormal karyotype: 46XY,+8,t(9;11)(p22;q23). FISH study revealed the presence of trisomy 8 clone also in the hypoplastic state. While MLL-AF9 chimeric mRNA was observed in leukemic cells, it was not detectable in bone marrow cells from the hypoplastic state by RT-PCR. This is the first report of a trisomy 8 clone which evolved into one with a MLL gene rearrangement.
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PMID:Clonal evolution to acute myeloblastic leukemia with MLL gene rearrangement from trisomy 8 clone. 926 97

The human ELL gene on chromosome 19p13.1 undergoes frequent translocations with the trithorax-like MLL gene on chromosome 11q23 in acute myeloid leukemia. Recently, the human ELL gene was shown to encode an RNA polymerase II elongation factor that activates elongation by suppressing transient pausing by polymerase at many sites along the DNA. In this report, we identify and characterize two overlapping ELL functional domains that govern its interaction with RNA polymerase II and the ternary elongation complex. Our findings reveal that, in addition to its elongation activation domain, ELL contains a novel type of RNA polymerase II interaction domain that is capable of negatively regulating polymerase activity in promoter-specific transcription initiation in vitro. Notably, the MLL-ELL translocation results in deletion of a portion of this functional domain, and ELL mutants lacking sequences deleted by the translocation bind RNA polymerase II and are fully active in elongation, but fail to inhibit initiation. Taken together, these results raise the possibility that the MLL-ELL translocation could alter ELL-RNA polymerase II interactions that are not involved in regulation of elongation.
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PMID:Structure and function of RNA polymerase II elongation factor ELL. Identification of two overlapping ELL functional domains that govern its interaction with polymerase and the ternary elongation complex. 926 87

CBP, which is located on 16p13 and encodes a transcriptional adaptor/coactivator protein, has been shown to fuse by the t(8;16)(p11;p13) translocation to MOZ on 8p11 in acute myeloid leukemia. We found a t(11;16)(q23;p13) in a child with therapy-related chronic myelomonocytic leukemia. Subsequent reverse transcriptase-polymerase chain reaction and direct sequencing analyses revealed the MLL-CBP fusion transcript in CMML cells. Because 11q23 translocations involving MLL and t(8;16) involving MOZ and CBP have been reported in therapy-related leukemias, both the MLL and CBP genes may be targets for topoisomerase II inhibitors. Accordingly, we believe that most t(11;16)-associated leukemias may develop in patients who have been treated with cytotoxic chemotherapy for primary malignant diseases.
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PMID:Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation. 929 Sep 55

The severe combined immunodeficient (SCID) mouse model is an important tool with which to study new strategies for treating hematologic neoplasia. For these experiments, a large number of human cell lines growing in SCID mice are a prerequisite. We describe a new Epstein-Barr virus (EBV)-positive B cell line, designated BEVA, with a complex karyotype including translocations t(14:18)(q32;q21) and t(4;11) (q21;q23) that meets this need. As demonstrated by Southern blot analysis, BCL2 at 18q21, but not MLL/ALL1 at 11q23, was involved in these translocations. BEVA cells coexpressed lymphoid (IgG-kappa, CD19, CD20, CD21, and CD24) and myeloid (CD11b, CD15, and CDw65) markers. Interestingly, the cell line was established from the bone marrow culture of a patient with acute myeloid leukemia (AML). Examination of bone marrow biopsy specimens suggested the presence of non-Hodgkin's lymphoma (NHL) in this patient in addition to AML. In vitro and in vivo growth characteristics of the BEVA cell line were compared with the previously described EBV-positive B cell line DoHH2, also carrying a translocation t(14;18)(q32;q21). These DoHH2 cells additionally expressed CD10, whereas, in contrast to BEVA cells, only a small population of DoHH2 cells showed expression of CD44. Both cell lines showed similar growth characteristics in vitro, but reacted differently to cytokines, including interleukin (IL)-4, IL-6, IL-7, and alpha-interferon (IFN). Upon inoculation in SCID mice, marked differences were observed in the dissemination patterns of the BEVA or DoHH2 cells. Although both cell lines circulated in the blood and were predominantly found in murine bone marrow and lymphoid tissues, DoHH2 cells infiltrated the murine spleens, whereas BEVA cells could only rarely be detected in these tissues. In contrast to DoHH2 cells, BEVA cells gave rise to tumor masses in liver, kidney, and para-aortal or mesenteric lymph nodes. The relationship between these in vitro differences and the observed differences in dissemination of both cell lines is discussed.
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PMID:Characterization of a novel malignant B cell line with t(14;18) and t(4;11) established from a patient with acute monoblastic leukemia. 929 3

A novel variant of the chimerical MLL-AF10 mRNA transcript was detected in a pediatric patient with acute myeloid leukemia (AML) by a new asymmetric reverse-transcription polymerase chain reaction (ART-PCR) method. Sequence analysis of the fusion region on the amplified cDNA fragment showed an in-frame joining of exon e5 of the MLL gene and position 1931 of the cDNA sequence of the AF10 gene, giving rise to a new MLL-AF10 transcript. The presence of the new chimerical mRNA product in a sample from the patient was confirmed by classical RT-PCR.
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PMID:A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. 930 18

Panhandle PCR amplifies genomic DNA with known 5' and unknown 3' sequences from a template with an intrastrand loop schematically shaped like a pan with a handle. We used panhandle PCR to clone MLL genomic breakpoints in two pediatric treatment-related leukemias. The karyotype in a case of treatment-related acute lymphoblastic leukemia showed the t(4;11)(q21;q23). Panhandle PCR amplified the translocation breakpoint at position 2158 in intron 6 in the 5' MLL breakpoint cluster region (bcr). The karyotype in a case of treatment-related acute myeloid leukemia was normal, but Southern blot analysis showed a single MLL gene rearrangement. Panhandle PCR amplified the breakpoint at position 1493 in MLL intron 6. Screening of somatic cell hybrid and radiation hybrid DNAs by PCR and reverse transcriptase-PCR analysis of the leukemic cells indicated that panhandle PCR identified a fusion of MLL intron 6 with a previously uncharacterized sequence in MLL intron 1, consistent with a partial duplication. In both cases, the breakpoints in the MLL bcr were in Alu repeats, and there were Alu repeats in proximity to the breakpoints in the partner DNAs, suggesting that Alu sequences were relevant to these rearrangements. This study shows that panhandle PCR is an effective method for cloning MLL genomic breakpoints in treatment-related leukemias. Analysis of additional pediatric cases will determine whether breakpoint distribution deviates from the predilection for 3' distribution in the bcr that has been found in adult cases.
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PMID:Panhandle PCR strategy to amplify MLL genomic breakpoints in treatment-related leukemias. 932 53

The MLL gene at chromosome 11, band q23, is involved in translocations with as many as 40 different chromosomal bands. Virtually all breakpoints occur within an 8.3 kb BamHI fragment and result in 5' MLL fused to partner genes in a 5'-3' orientation. The translocation t(9;11)(p22;q23), which results in the fusion of MLL to AF9, is the most common of the 11q23 chromosomal abnormalities observed in de novo acute myeloid leukemia (AML), in therapy related leukemia (t-AML), and rarely in acute lymphoblastic leukemia (ALL). We have studied 24 patients with a t(9;11) and an MLL rearrangement, including 19 patients with AML, four with t-AML, and one with ALL. To understand the mechanisms of this illegitimate recombination, we cloned and sequenced the t(9;11) translocation breakpoint junctions on both derivative chromosomes from one AML patient and from the Mono Mac 6 (MM6) cell line, which was derived from a patient with AML. Two different complex junctions were noted. In the AML patient, both chromosome 11 and 9 breaks were staggered, occurred in Alu DNA sequences, and resulted in a 331 bp duplication. In the MM6 cell line, breaks in chromosomes 11 and 9 were also staggered, but, in contrast to the finding in the AML patient, the breaks did not involve Alu DNA sequences and resulted in a 664 bp deletion at the breakpoints. Using reverse transcriptase (RT-) PCR, we analyzed 11 patient samples, including the two just described, for MML-AF9 fusions. The fusion occurred in six of seven AML patients, two of two t-AML patients, one patient with ALL, and in the MM6 cell line. Interestingly, all of the breaks within the AF9 gene in AML patients occurred in the central AF9 exon, called Site A by others, whereas in the single ALL patient the breakpoint mapped to a more 3' region of the AF9 gene. Our data, when combined with those of others, suggest that the fusion point within the AF9 gene, and thus the amount of AF9 material included in the MLL-AF9 fusion gene product, may influence the phenotype of the resulting leukemia. This further supports the proposal that the MML translocation partner genes play a critical role in the leukemogenic process.
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PMID:Identification of complex genomic breakpoint junctions in the t(9;11) MLL-AF9 fusion gene in acute leukemia. 933 69

Fusion genes implicating the MLL gene have been recently demonstrated in various 11q23 chromosomal abnormalities in human hematopoietic malignancies. We analyzed a t(6;11)(q21;q23) translocation detected in a secondary acute myeloblastic leukemia. This translocation results in fusion of the MLL gene on 11q23 to a previously unknown gene on chromosome 6 that differs from the previously reported MLL partner gene AF6q. The novel gene, named AF6q21, encodes a forkhead (FH) protein with strong similarities to the two FH family members whose genes are already known to be involved in chromosomal translocations of human malignancies, AFX and FKHR. Strikingly, in these translocations the breakpoints are located at the same position within the FH domains. Therefore, AF6q21, AFX, and FKHR could define a new FH subfamily particularly involved in human malignancies.
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PMID:AF6q21, a novel partner of the MLL gene in t(6;11)(q21;q23), defines a forkhead transcriptional factor subfamily. 934 57

Trisomy 11 is uncommon in acute myeloid leukemia (AML) and molecular studies have shown partial tandem duplication of the MLL gene in some cases. In a case of AML with trisomy 11, the MLL gene was found to be tandemly duplicated, leading to the formation of a fusion transcript involving splicing of exon 8 to exon 2. Fluorescence in situ hybridization revealed two populations of blasts, with about two-thirds of them showing trisomy 11. These findings suggested that the trisomic and non-trisomic clones had evolved from a clone with a common submicroscopic mutation. As recent studies showed that MLL gene duplication in fact occurs more often as a primary mutation in the absence of trisomy 11, it is possible that in our case the MLL gene duplication might be the common underlying mutation. The clinical course of this case was similar to the poor prognosis reported for trisomy 11.
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PMID:Acute myeloid leukemia with trisomy 11: a molecular cytogenetic study. 935 91


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