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 gene rearrangements identify a subgroup of acute leukemias with a bad prognosis. Fifty-one adult patients with de novo AML were screened for MLL rearrangements by Southern blot. An unexpected high frequency of AML-M2 according to the FAB classification was found. The most striking morphologic features of these cases were the scarcity of Auer rods and granulocytic dysplasia. Morphologic traits could be helpful in distinguishing molecular groups of AML-M2.
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PMID:Adult de novo acute myeloid leukemias with MLL rearrangements. 1037 52

To explore the possibility that deregulated HOX gene expression might commonly occur during leukemic hematopoiesis, we compared the relative levels of expression of these and related genes in phenotypically and functionally defined subpopulations of AML blasts and normal hematopoietic cells. Initially, a semi-quantitative RT-PCR technique was used to amplify total cDNA from total leukemic blast cell populations from 20 AML patients and light density cells from four normal bone marrows. Expression of HOX genes (A9, A10, B3 and B4), MEIS1 and MLL was easily detected in the majority of AML samples with the exception of two samples from patients with AML subtype M3 (which expressed only MLL). Low levels of HOXA9 and A10 but not B3 or B4 were seen in normal marrow while MLL was easily detected. PBX1a was difficult to detect in any AML sample but was seen in three of four normal marrows. Cells from nine AML patients and five normal bone marrows were FACS-sorted into CD34+CD38-, CD34+CD38+ and CD34-subpopulations, analyzed for their functional properties in long-term culture (LTC) and colony assays, and for gene expression using RT-PCR. 93 +/- 14% of AML LTC-initiating cells, 92 +/- 14% AML colony-forming cells, and >99% of normal LTC-IC and CFC were CD34+. The relative level of expression of the four HOX genes in amplified cDNA from CD34- as compared to CD34+CD38- normal cells was reduced >10-fold. However, in AML samples this down-regulation in HOX expression in CD34- as compared to CD34+CD38- cells was not seen (P < 0.05 for comparison between AML and normal). A similar difference between normal and AML subpopulations was seen when the relative levels of expression of MEIS1, and to a lesser extent MLL, were compared in CD34+ and CD34- cells (P < 0.05). In contrast, while some evidence of down-regulation of PBX1a was found in comparing CD34- to CD34+ normal cells it was difficult to detect expression of this gene in any subpopulation from most AML samples. Thus, the down-regulation of HOX, MEIS1 and to some extent MLL which occurs with normal hematopoietic differentiation is not seen in AML cells with similar functional and phenotypic properties.
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PMID:Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. 1037 71

The MLL gene from human chromosome 11q23 is involved in >30 different chromosomal translocations resulting in a plethora of different MLL fusion proteins. Each of these tends to associate with a specific leukaemia type, for example, MLL-AF9 is found mainly in acute myeloid leukaemia. We have studied the role of the Mll-AF9 gene fusion made in mouse embryonic stem cells by an homologous recombination knock-in. Acute leukaemias developed in heterozygous mice carrying this fusion as well as in chimeric mice. As with human chromosomal translocation t(9;11), the majority of cases were acute myeloid leukaemias (AMLs) involving immature myeloblasts, but a minority were acute lymphoblastic leukaemia. The AMLs were preceded by effects on haematopoietic differentiation involving a myeloproliferation resulting in accumulation of Mac-1/Gr-1 double-positive mature myeloid cells in bone marrow as early as 6 days after birth. Therefore, non-malignant expansion of myeloid precursors is the first stage of Mll-AF9-mediated leukaemia followed by accumulation of malignant cells in bone marrow and other tissues. Thus, the late onset of overt tumours suggests that secondary tumorigenic mutations are necessary for malignancy associated with MLL-AF9 gene fusion and that myeloproliferation provides the pool of cells in which such events can occur.
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PMID:The mll-AF9 gene fusion in mice controls myeloproliferation and specifies acute myeloid leukaemogenesis. 1039 73

Acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in infants have in common a high incidence of translocations of the MLL gene at chromosome band 11q23. Similar translocations occur in leukemias associated with chemotherapies that target DNA topoisomerase II. MLL has numerous different partner genes. The role of the many MLL fusion proteins in leukemogenesis is not yet understood. The t(4;11) translocation, the most common translocation in infant ALL, adversely affects the outcome. Additional genetic changes, especially Ikaros alterations, are found in infant ALL. Other forms of myeloid leukemia in infants present as myelodysplastic and myeloproliferative syndromes, which may be associated with constitutional disorders. This review will consider all leukemia in infants, but will focus on leukemias with MLL gene translocations.
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PMID:Leukemia in infants. 1039 90

The molecular characterization of childhood leukemias directly affects our treatment strategies. Acute lymphoblastic leukemia patients with the TEL-AML1 fusion have a favorable prognosis, whereas those with the E2A-PBX1 fusion require more intensive therapy to obtain a good outcome. Acute lymphoblastic leukemia patients whose leukemic lymphoblasts contain the MLL-AF4 or the BCR-ABL fusion are often candidates for allogeneic hematopoietic stem cell transplantation during first remission. Among acute myeloid leukemia patients, AML1-ETO and CBFbeta-MYH11 fusions are associated with a favorable response, especially when the chemotherapy regimen includes high-dose cytarabine. Patients with acute promyelocytic leukemia who carry the PML-RAR alpha fusion respond to all-trans retinoic acid and have an excellent outcome after treatment with all-trans retinoic acid in combination with anthracyclines. Several novel therapeutic agents targeted to molecular lesions of leukemic cells are under investigation.
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PMID:Molecular diagnostics in the treatment of leukemia. 1040 Mar 71

Of 29 infants with acute myeloid leukemia (AML), 14 (48%) had various 11q23 translocations. MLL rearrangements were examined in 21 of the 29 patients, and 11 (52%) showed the rearrangements. 11q23 translocations and/or MLL rearrangements were found in 17 (58%) of the 29 patients. While all but one of the 17 patients with 11q23/MLL rearrangements had M4 or M5 type of the FAB classification, the 12 patients without such rearrangements had various FAB types, including M2, M4, M4EO, M6 and M7. Of the 12 patients with other chromosome abnormalities or normal karyotypes, two had inv(16) ort(16;16), one had t(1;22)(p13;q13), and two had a novel translocation, t(7;12)(q32;p13). The breakpoint on 12p of the t(7;12) was assigned to intron 1 or the region just upstream of exon 1 of the TEL/ETV6 gene by fluorescence in situ hybridization. The event-free survival at 5 years for the 17 patients with 11q23/MLL rearrangements was 42.2%, and that for the 12 patients without such rearrangements was 31.3% (P = 0.5544). 11q231MLL rearrangements have been frequently reported and a poor prognosis in infant acute lymphoblastic leukemia implied. Our study showed that while 11q23/MLL rearrangements were also common in infant AML, AML infants with such rearrangements had a clinical outcome similar to that of AML infants without such rearrangements.
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PMID:Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. 1040 Apr 16

Presence of specific chromosomal abnormalities is one of the most important prognostic factors in acute myeloid leukemia (AML). Recent advances in molecular biology have allowed structural and functional characterization of many of these genomic rearrangements. In many instances, AML is associated with gene fusion, whereby segments from two different genes fuse to give rise to a chimeric structure consisting of the 5' end of one gene and the 3' end of another. Recombinant DNA technology has also permitted the creation of animal models for in vivo studies of the leukemogenic role of several of these chimeric proteins. This review presents current information on the molecular biology and the clinical significance of three of the most common molecular subtypes of AML. In the first two, t(8;21)(q22;q22) and inv(16)(p13q22), disruption of genes encoding for subunits of core-binding factor (CBF), a transcriptional regulator of normal hematopoiesis, occurs, suggesting a common leukemogenic pathway. The third subgroup is characterized by disruption of MLL, a gene that is located at chromosome band 11q23 and encodes a putative transcriptional regulator. This gene is commonly involved in reciprocal translocations of chromosome 11q23 with other gene partners, but, in some instances, MLL disruption occurs by a mechanism of partial tandem duplication, in the absence of any other partner gene. Current data suggest that identification of specific genetic abnormalities in newly diagnosed AML patients is important to predict clinical outcome and, perhaps, to select different therapeutic strategies. The predictive value of detecting these molecular markers to predict cure or relapse in AML patients in complete remission following definitive treatment is still uncertain.
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PMID:Core-binding factor (CBF) and MLL-associated primary acute myeloid leukemia: biology and clinical implications. 1042 27

The place of FISH in the monitoring of minimal residual disease (MRD) is yet to be fully characterised. Routine bone marrow cytogenetics at diagnosis in a 22 year old patient with acute myeloid leukemia FAB type M5 detected a translocation t(9;11)(p22;q23). We report our investigations to assess residual levels of translocation using a FISH probe designed to detect a gene split by the translocation. We used MLL (Oncor), a probe which spans the MLL gene at 11q23, in both metaphase and interphase preparations. At diagnosis, metaphase FISH showed 3 distinct cell lines-normal with 2 signals, abnormal with 3 signals and abnormal with 2 signals, while interphase FISH showed only 2 cell lines, one with 2 signals (which could be normal or abnormal) and one with 3 signals (split MLL). Following treatment, with the patient in clinical remission, 7 further cytogenetic analyses and 2 further FISH analyses were compared. Our results suggest that monitoring of the t(9;11) by metaphase FISH is feasible and straightforward compared to cytogenetics but interphase FISH may be problematic.
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PMID:Comparison of metaphase and interphase FISH monitoring of minimal residual disease with MLL gene probe: case study of AML with t(9;11). 1043 26

A case of acute myeloid leukemia (M2) with double minute chromosomes and complex karyotypic abnormalities was analyzed cytogenetically and molecularly. Comparative genomic hybridization (CGH) showed that the 8q24 region that contains the MYC oncogene was not amplified. Instead, amplification of chromosomal regions 11q23-->qter and 9p11-->pter was identified. Southern blot analysis confirmed the CGH findings and showed that the ETS1, FLI1, SRPR, NFRKB, and KCNJ5 genes located at 11q23-->24 were amplified, whereas the MLL at 11q23 was not amplified. Additionally, the IFN beta 1 and CDKN2A genes at 9p were amplified, but to a lesser degree. This is the first example of a case of acute myeloid leukemia with double minute chromosomes that has not involved amplification of either the MYC or the MLL genes.
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PMID:Identification of amplified genes in a patient with acute myeloid leukemia and double minute chromosomes. 1048 78

The t(11;17) has been described in patients with acute myeloid leukemia (AML), and the AF17 gene was previously cloned as a fusion partner of the MLL gene in t(11;17)(q23;q21)-AML. We analyzed one patient with de novo AML and one with therapy-related AML with t(11;17)(q23;q25) and identified the AF17q25 gene on chromosome 17q25, a putative septin family gene, fused with MLL. AF17q25 encoded at least three kinds of proteins [type I (568 a.a.), type II (594 a.a.), and type III (574 a.a.)] that contained two kinds of different amino acid sequences at the COOH terminus. The MLL-AF17q25 fusion transcript consisted of type I AF17q25 transcript. The AF17q25 protein is homologous to septin family proteins, including H5, NEDD5, CDC10, and hCDCrel, which is one of the fusion partners of MLL in t(11;22)(q23;q11)-AML. These results suggest that AF17q25 and hCDCrel might define a new septin family particularly involved in the pathogenesis of 11q23-associated leukemia.
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PMID:AF17q25, a putative septin family gene, fuses the MLL gene in acute myeloid leukemia with t(11;17)(q23;q25). 1048 69


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