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)

MLL (ALL-1) chimeric fusions and MLL partial tandem duplications (PTD) may have mechanistically distinct contributions to leukemogenesis. Acute myeloid leukemia (AML) blasts with the t(9;11)(p22; q23) express MLL-AF9 and MLL wild-type (WT) transcripts, while normal karyotype AML blasts with the MLL(PTD/WT) genotype express MLL PTD but not the MLL WT. Silencing of MLL WT in MLL(PTD/WT) blasts was reversed by DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibitors, and MLL WT induction was associated with selective sensitivity to cell death. Reduction of MLL PTD expression induced MLL WT and reduced blast colony-forming units, supporting opposing functions for MLL PTD and MLL WT whereby the MLL PTD contributes to the leukemic phenotype via a recessive gain-of-function. The coincident suppression of the MLL WT allele with the expression of the MLL PTD allele, along with the functional data presented here, supports the hypothesis that loss of WT MLL function via monoallelic repression contributes to the leukemic phenotype by the remaining mutant allele. These data from primary AML and the pharmacologic reversal of MLL WT silencing associated with a favorable alteration in the threshold for apoptosis suggest that these patients with poor prognosis may benefit from demethylating or histone deacetylase inhibitor therapy, or both.
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PMID:The MLL partial tandem duplication: evidence for recessive gain-of-function in acute myeloid leukemia identifies a novel patient subgroup for molecular-targeted therapy. 1577 15

The pathological consequences resulting from deregulation of the apoptotic program include cancer (too little apoptosis) or diseases of cell deprivation, such as Alzheimer's (too much apoptosis). We have identified an additional pathology whereby cells reaching the earliest stage of chromatin cleavage have the potential to suppress apoptotic execution and survive. One specific cleavage event associated with this process is restricted to a location within the mixed lineage leukemia (MLL) gene at 11q23. The site of cleavage is consistent with the location where large, approximately 50 kbp loops of supercoiled DNA are attached to the nuclear matrix. Cells modified by this process generate MLL translocations, as shown by inverse PCR, that survive for days to weeks but which have no known relationship with clinical disease. Using a specific approach, cells stimulated by anti-CD95 antibody, a potent stimulator of the apoptotic program, facilitated creation of the MLL-AF9 fusion gene. Further, this rearrangement, which is commonly observed in patients with AML linked to exposure to cytotoxic agents, was efficiently transcribed in cells that were able to undergo cell division. These data are discussed in the context of benzene and benzene metabolite toxicity that impacts the process of apoptosis and is known to lead to leukemic disease.
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PMID:Surviving apoptosis: a possible mechanism of benzene-induced leukemia. 1593 15

The human AF9/MLLT3 gene is a common fusion partner for the MLL gene in translocations t(9;11)(p22;q23) associated with acute myeloid leukemia and acute lymphocytic leukemia. The exact function of the gene is still unknown, although a mouse knock-out model points to a role as a controller of embryo patterning. We report the case of a constitutional translocation t(4;9)(q35;p22) disrupting the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia and epilepsy. Array-CGH analysis at 1 Mbase resolution did not reveal any additional deletions/duplications. We hypothesize a loss-of-function mutation of the AF9/MLLT3 gene, and a possible role for the FAT gene on chromosome 4, in the genesis of the proband's severe neurological phenotype.
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PMID:Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy. 1600 Dec 62

The MLL-AF9 oncogene originates from the translocation t(9;11)(p22;q23), which is mainly associated with monocytic acute myeloid leukaemia (AML-M5; FAB-classification). In AML-M5 THP-1 cells carrying t(9;11) (p22;q23) and expressing MLL-AF9, we previously showed that MLL-AF9 expression is down-regulated during monocyte-macrophage maturation. We have subsequently observed that in a 'rapid-growing' variant of the THP-1 cell line (THP-1-R) MLL-AF9 down-regulation does not occur. MLL fusion proteins (including MLL-AF9) deregulate MYC transactivation activity, and both presence and absence of MYC down-regulation have been reported during monocyte-macrophage maturation in THP-1 cells. In the present study, we analyze the expression patterns of MLL-AF9, MLL wild-type and MYC after induction of monocyte-macrophage terminal differentiation in the AML-M5 cell lines, THP-1, THP-1-R, Mono-Mac-6 (MM6) and MOLM-13, all of which carry t(9;11)(p22;q23) and express MLL-AF9. RT-PCR analysis indicated that down-regulation of MLL-AF9, MLL or MYC is not necessary to abolish malignant phenotypes by induction of terminal monocyte-macrophage differentiation in leukaemic cells carrying t(9;11)(p22;q23).
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PMID:Down-regulation of MLL-AF9, MLL and MYC expression is not obligatory for monocyte-macrophage maturation in AML-M5 cell lines carrying t(9;11)(p22;q23). 1632 57

The fusion transcripts of MLL rearrangement [MLL(+)] in acute myeloid leukemia (AML) and their clinicohematologic correlation have not be well characterized in the previous studies. We used Southern blot analysis to screen MLL(+) in de novo AML. Reverse transcriptase-polymerase chain reaction was used to detect the common MLL fusion transcripts. cDNA panhandle PCR was used to identify infrequent or unknown MLL partner genes. MLL(+) was identified in 114 (98 adults) of 988 AML patients. MLL fusion transcripts comprised of 63 partial tandem duplication of MLL (MLL-PTD), 14 MLL-AF9, 9 MLL-AF10, 9 MLL-ELL, 8 MLL-AF6, 4 MLL-ENL and one each of MLL-AF1, MLL-AF4, MLL-MSF, MLL-LCX, MLL-LARG, MLL-SEPT6 and MLL-CBL. The frequency of MLL-PTD was 7.1% in adults and 0.9% in children (P<0.001). 11q23 abnormalities were detected in 64% of MLL/t11q23 and in none of MLL-PTD by conventional cytogenetics. There were no differences in remission rate, event-free survival and overall survival between adult MLL-PTD and MLL/t11q23 groups. Adult patients had a significantly poorer outcome than children. The present study showed that cDNA panhandle PCR can identify all rare or novel MLL partner genes. MLL-PTD was rare in childhood AML. MLL(+) adults had a poor outcome with no difference in survival between MLL-PTD and MLL/t11q23 groups.
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PMID:Characterization of fusion partner genes in 114 patients with de novo acute myeloid leukemia and MLL rearrangement. 1634 Oct 46

Recurring chromosome abnormalities are strongly associated with certain subtypes of leukemia, lymphoma and sarcomas. More recently, their potential involvement in carcinomas, i.e. prostate cancer, has been recognized. They are among the most important factors in determining disease prognosis, and in many cases, identification of these chromosome abnormalities is crucial in selecting appropriate treatment protocols. Chromosome translocations are frequently observed in both de novo and therapy-related acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The mechanisms that result in such chromosome translocations in leukemia and other cancers are largely unknown. Genomic breakpoints in all the common chromosome translocations in leukemia, including t(4;11), t(9;11), t(8;21), inv(16), t(15;17), t(12;21), t(1;19) and t(9;22), have been cloned. Genomic breakpoints tend to cluster in certain intronic regions of the relevant genes including MLL, AF4, AF9, AML1, ETO, CBFB, MYHI1, PML, RARA, TEL, E2A, PBX1, BCR and ABL. However, whereas the genomic breakpoints in MLL tend to cluster in the 5' portion of the 8.3 kb breakpoint cluster region (BCR) in de novo and adult patients and in the 3' portion in infant leukemia patients and t-AML patients, those in both the AML1 and ETO genes occur in the same clustered regions in both de novo and t-AML patients. These differences may reflect differences in the mechanisms involved in the formation of the translocations. Specific chromatin structural elements, such as in vivo topoisomerase II (topo II) cleavage sites, DNase I hypersensitive sites and scaffold attachment regions (SARs) have been mapped in the breakpoint regions of the relevant genes. Strong in vivo topo II cleavage sites and DNase I hypersensitive sites often co-localize with each other and also with many of the BCRs in most of these genes, whereas SARs are associated with BCRs in MLL, AF4, AF9, AML1, ETO and ABL, but not in the BCR gene. In addition, the BCRs in MLL, AML1 and ETO have the lowest free energy level for unwinding double strand DNA. Virtually all chromosome translocations in leukemia that have been analyzed to date show no consistent homologous sequences at the breakpoints, whereas a strong non-homologous end joining (NHEJ) repair signature exists at all of these chromosome translocation breakpoint junctions; this includes small deletions and duplications in each breakpoint, and micro-homologies and non-template insertions at genomic junctions of each chromosome translocation. Surprisingly, the size of these deletions and duplications in the same translocation is much larger in de novo leukemia than in therapy-related leukemia. We propose a non-homologous chromosome recombination model as one of the mechanisms that results in chromosome translocations in leukemia. The topo II cleavage sites at open chromatin regions (DNase I hypersensitive sites), SARs or the regions with low energy level are vulnerable to certain genotoxic or other agents and become the initial breakage sites, which are followed by an excision end joining repair process.
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PMID:Chromatin structural elements and chromosomal translocations in leukemia. 1689 85

Using a mouse model of human acute myeloid leukemia (AML) induced by the MLL-AF9 oncogene, we demonstrate that colony-forming cells (CFCs) in the bone marrow and spleen of leukemic mice are also leukemia stem cells (LSCs). These self-renewing cells (1) are frequent, accounting for 25%-30% of myeloid lineage cells at late-stage disease; (2) generate a phenotypic, morphologic, and functional leukemia cell hierarchy; (3) express mature myeloid lineage-specific antigens; and (4) exhibit altered microenvironmental interactions by comparison with the oncogene-immortalized CFCs that initiated the disease. Therefore, the LSCs responsible for sustaining, expanding, and regenerating MLL-AF9 AML are downstream myeloid lineage cells, which have acquired an aberrant Hox-associated self-renewal program as well as other biologic features of hematopoietic stem cells.
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PMID:Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. 1704 2

Rearrangements of the MLL gene are significant in acute leukemia. Among the most frequent translocations are t(4;11)(q21;q23) and t(9;11)(p22;q23), which give rise to the MLL-AFF1 and MLL-MLLT3 fusion genes (alias MLL-AF4 and MLL-AF9) in acute lymphoblastic and acute myeloid leukemia, respectively. Current evidence suggests that determining the MLL status of acute leukemia, including precise identification of the partner gene, is important in defining appropriate treatment. This underscores the need for accurate detection methods. A novel molecular diagnostic device, the MLL FusionChip, has been successfully used to identify MLL fusion gene translocations in acute leukemia, including the precise breakpoint location. This study evaluated the performance of the MLL FusionChip within a routine clinical environment, comprising nine centers worldwide, in the analysis of 21 control and 136 patient samples. It was shown that the assay allowed accurate detection of the MLL fusion gene, regardless of the breakpoint location, and confirmed that this multiplex approach was robust in a global multicenter trial. The MLL FusionChip was shown to be superior to other detection methods. The type of molecular information provided by MLL FusionChip gave an indication of the appropriate primers to design for disease monitoring of MLL patients following treatment.
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PMID:A multicenter evaluation of comprehensive analysis of MLL translocations and fusion gene partners in acute leukemia using the MLL FusionChip device. 1728 65

Multiplex reverse transcription-polymerase chain reaction (M-RT-PCR) has been proved to possess great clinical potential for simultaneous screening of 29 chromosomal translocations in acute leukemia. To evaluate the clinical value of M-RT-PCR in hematologic malignancies, bone marrow samples from 90 patients with various hematologic malignancies, including 25 acute myelogenous leukemia (AML), 22 acute lymphoblastic leukemia (ALL), 27 chronic myelogenous leukemia (CML), 4 myeloproliferative diseases (MPD), 3 chronic lymphoblastic leukemia (CLL), 3 non-Hodgkin's lymphoma (NHL), 3 myelodysplastic syndrome (MDS), 2 multiple myeloma (MM) and 1 malignant histiocytosis (MH) were subjected to both M-RT-PCR and chromosome karyotypic analysis. Some of cases were subjected to follow-up examination of M-RT-PCR during the period of clinical complete remission (CR) for detection of minimal residual leukemia. In our hand, 12 of 29 chromosomal translocation transcripts including TEL/PDGFR, DEK/CAN, MLL/AF6, AML1/ETO, MLL/AF9, BCR/ABL, MLL/MLL, PML/RARu, TLS/ERG, E2A/HLF, EVI1 and HOXI1 were detected in 57 cases (63.3 %) of the 90 samples, which were in consistency with the results of karyotypic analysis. Furthermore, M-RT-PCR had also shown good clinical relevance when used as an approach to detect minimal residual leukemia. We concluded that M-RT-PCR could be used as an efficient and fast diagnostic tool not only in the initial diagnosis of hematologic malignancies but also in subsequent monitor of minimal residual leukemia.
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PMID:Multiplex reverse transcription-polymerase chain reaction for simultaneous screening of 29 chromosomal translocation in hematologic malignancies. 1735 82

Human leukemias harboring chromosomal translocations involving the mixed lineage leukemia (MLL, HRX, ALL-1) gene possess high-level expression, and frequent activating mutations of the receptor tyrosine kinase FLT3. We used a murine bone marrow transplant model to assess cooperation between MLL translocation and FLT3 activation. We demonstrate that MLL-AF9 expression induces acute myelogenous leukemia (AML) in approximately 70 days, whereas the combination of MLL-AF9 and FLT3-ITD does so in less than 30 days. Secondary transplantation of splenic cells from diseased mice established that leukemia stem cells are present at a very high frequency of approximately 1:100 in both diseases. Importantly, prospectively isolated granulocyte macrophage progenitors (GMPs) coinfected with MLL-AF9 and FLT3-ITD give rise to a similar AML, with shorter latency than from GMP transduced with MLL-AF9 alone. Cooperation between MLL-AF9 and FLT3-ITD was further verified by real-time assessment of leukemogenesis using noninvasive bioluminescence imaging. We used this model to demonstrate that MLL-AF9/FLT3-ITD-induced leukemias are sensitive to FLT3 inhibition in a 2-3 week in vivo assay. These data show that activated FLT3 cooperates with MLL-AF9 to accelerate onset of an AML from whole bone marrow as well as a committed hematopoietic progenitor, and provide a new genetically defined model system that should prove useful for rapid assessment of potential therapeutics in vivo.
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PMID:MLL-AF9 and FLT3 cooperation in acute myelogenous leukemia: development of a model for rapid therapeutic assessment. 1785 51


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