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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute myeloid leukemias (AMLs) are consistently associated with chromosomal rearrangements that result in the generation of chimeric genes and fusion proteins. One of the two affected genes is frequently a transcription factor Involved in the regulation of hematopoletic differentiation. Recent findings suggest a common leukemogenic mechanism for the fused transcription factor: abnormal recruitment of histone deacetylase (HDAC)-containing complexes to its target promoters. Inhibition of HDAC enzymatic activity reverts the leukemic phenotype in vitro and therefore represents a plausible strategy for antileukemic therapy. In this review, we first briefly describe the molecular structure and mechanisms of the most frequent AML associated fusion proteins (RAR, MLL, and CBF fusions) and then summarize available knowledge about their effects on the nuclear architecture. We propose that alteration of nuclear compartmentalization might represent an additional common mechanism of leukemogenesis.
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PMID:Effects of the acute myeloid leukemia--associated fusion proteins on nuclear architecture. 1117 39

Two distinct clinical syndromes have been associated with the p11.12 region of the short arm of chromosome 8: stem-cell myeloproliferative disorder (B-or T-cell lymphoblastic leukemia/lymphoma with myeloid hyperplasia and peripheral blood eosinophilia) and acute myeloid leukemia (myelomonocytic or monocytic with erythrophagocytosis). The FGFR1 and MOZ genes are rearranged in these diseases and encode one of the four fibroblast growth factor receptors and a member of a novel histone acetyltransferase family, respectively. The predicted fusion proteins that are putatively oncogenic - FOP-FGFR1, CEP110-FGFR1, and FIM-FGFR1 - and - MOZ-CBP, MOZ-p300, and MOZ-TIF2 - lead to tumorigenesis through distinct pathways. The constitutive kinase activity triggered by dimerization mediated by the protein-protein interaction motifs of the FGFR1 protein partner regardless of external stimuli and the delocalization of the fusion proteins compared to their normal counterparts may lead to tumorigenesis presumably by inducing inappropriate recruitment in the cytoplasm of signaling substrates. Currently, little is known about the precise role of MOZ in the regulation of gene transcription. However, all the aberrant proteins described to date retain the MOZ histone acetyltransferase domain fused to that of the transcription coactivators CBP, p300, and TIF2. The fusion of two acetyltransferases whose activity may be mistargetted or misregulated could be a critical event in leukemogenesis. The increasing number of translocations affecting FGFR1 and MOZ strongly suggest their involvement in oncogenic processes and point to these proteins as potential therapeutical targets.
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PMID:[FGFR1 and MOZ, two key genes involved in malignant hemopathies linked to rearrangements within the chromosomal region 8p11-12]. 1117 18

Histone acetyltransferase p300 functions as a transcriptional co-activator which interacts with a number of transcription factors. Monocytic leukemia zinc finger protein (MOZ) has histone acetyltransferase activity. We report the fusion of the MOZ gene to the p300 gene in acute myeloid leukemia with translocation t(8;22)(p11;q13). FISH and Southern blot analyses showed the rearrangement of the MOZ and p300 genes. We determined the genomic structure of the p300 and the MOZ genes and the breakpoints of the translocation. Analysis of fusion transcripts indicated that the zinc finger and acetyltransferase domains of MOZ are fused to a largely intact p300. These results suggest that MOZ-p300, which has two acetyltransferase domains, could be involved in leukemogenesis through aberrant regulation of histone acetylation.
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PMID:Fusion of MOZ and p300 histone acetyltransferases in acute monocytic leukemia with a t(8;22)(p11;q13) chromosome translocation. 1124 5

AML1 is a transcription factor that is essential for normal hematopoietic development. It is the most frequent target for translocations in acute leukemia. Recently, fluorescence in situ hybridization was used to identify a novel syndrome of radiation-associated secondary acute myelogenous leukemia that had AML1 translocations. Using polymerase chain reaction, the AML1 fusion transcript was isolated from the patient who had a t(19;21) radiation-associated leukemia. The AML1 gene is fused out of frame to chromosome 19 sequences, resulting in a truncated AML protein bearing the DNA binding domain but not the transcriptional activation domain. This fusion AML1 protein functions as an inhibitor of the normal AML1 protein. (Blood. 2001;97:2168-2170)
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PMID:Fusion AML1 transcript in a radiation-associated leukemia results in a truncated inhibitory AML1 protein. 1126 87

Transgenic mice have been used to explore the role of chromosomal translocations in the genesis of tumors. But none of these efforts has actually involved induction of a translocation in vivo. Here we report the use of Cre recombinase to replicate in vivo the t(8;21) translocation found in human acute myeloid leukemia (AML). As in the human tumors, the murine translocation fuses the genes AML1 and ETO. We used homologous recombination to place loxP sites at loci that were syntenic with the break points for the human translocation. Cre activity was provided in mice by a transgene under the control of the Nestin promoter, or in cultured B cells by infecting with a retroviral vector encoding Cre. In both instances, Cre activity mediated interchromosomal translocations that fused the AML1 and ETO genes. Thus, reciprocal chromosomal translocations that closely resemble rearrangements found in human cancers can be achieved in mice.
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PMID:Inducible chromosomal translocation of AML1 and ETO genes through Cre/loxP-mediated recombination in the mouse. 1126 49

In chromosomal rearrangements of acute myeloid leukaemia patients the mixed lineage leukaemia (MLL) gene, a human homolog of the Drosophila gene trithorax, is frequently fused to AF10. Here we describe the identification and a functional characterization of the Drosophila homolog dAF10. We show that dAF10 functions in heterochromatin-dependent genomic silencing of position effect variegation, a phenomenon associated with chromosomal rearrangements that cause mosaic expression of euchromatic genes when relocated next to heterochromatin. We also demonstrate that dAF10 can associate with the heterochromatin protein 1 (HP1) in vitro and in vivo. The results indicate that dAF10 is an HP1-interacting component of the heterochromatin-dependent gene silencing pathway, which either contributes to the stability of the heterochromatin complex or to its function.
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PMID:The Drosophila homolog of the human AF10 is an HP1-interacting suppressor of position effect variegation. 1126 62

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
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PMID:Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). 1143 29

This study describes the processing of human tumor cells or cell membranes to express alpha-gal epitopes (Galalpha1-3Gal-beta1-4GlcNAc-R) by the use of New World monkey (marmoset) recombinant alpha1,3galactosyltransferase (ralpha1,3GT), produced in the yeast Pichia pastoris. Such tumor cells and membranes may serve, in cancer patients, as autologous tumor vaccines that are targeted in vivo to antigen-presenting cells by the anti-Gal antibody. This ralpha1,3GT lacks transmembrane and cytoplasmic domains, ensuring its solubility without detergent. It is effectively produced in P. pastoris under constitutive expression of the P(GAP) promoter and is secreted into the culture medium in a soluble, truncated form fused to a (His)(6) tag. This tag enables the simple affinity purification of ralpha1,3GT on a nickel-Sepharose column and elution with imidazole. The purified enzyme appears in SDS-PAGE as two bands with the size of 40 and 41 kDa and displays the same acceptor specificity as the mammalian native enzyme. ralpha1,3GT is very effective in synthesizing alpha-gal epitopes on membrane-bound carbohydrate chains and displays a specific activity of 1.2 nM membrane bound alpha-gal epitopes/min/mg. Incubation of very large amounts of human acute myeloid leukemia cells (1 x 10(9 )cells) with neuraminidase, ralpha1,3GT, and UDP-Gal resulted in the synthesis of approximately 6 x 10(6 )alpha-gal epitopes per cell. Effective synthesis of alpha-gal epitopes could be achieved also with as much as 2 g cell membranes prepared from the tumor of a patient with ovarian carcinoma. These data imply that ralpha1,3GT produced in P. pastoris is suitable for the synthesis of alpha-gal epitopes on bulk amounts of tumor cells or cell membranes required for the preparation of autologous tumor vaccines.
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PMID:Synthesis of alpha-gal epitopes (Galalpha1-3Galbeta1-4GlcNAc-R) on human tumor cells by recombinant alpha1,3galactosyltransferase produced in Pichia pastoris. 1144 37

The MLL (HRX, ALL-1 HTRX) gene at chromosome band 11q23 frequently is rearranged in acute lymphoblastic and myeloblastic leukemia. To date, more than 40 different 11q23 abnormalities have been described on the cytogenetic level, and at least 25 of the respective fusion partner genes are cloned. The vast majority of the respective reciprocal translocations generate a chimeric 5'-MLL/partner-3' gene on the derivative 11q23. In this work, we report a unique ins(X;11)(q24;q23) in an infant with acute myeloid leukemia (AML-M2) that fuses the human KIAA0128 gene at Xq24 with MLL. In contrast to the typical reciprocal MLL translocations, however, we provide evidence that the 5'-MLL/KIAA0128-3' fusion resides on Xq24 rather than on 11q23. The KIAA0128 gene encodes the human Septin 6 protein, which contains an ATP-GTP binding motif and three nuclear targeting sequences in its carboxy terminus. The maintenance of the reading frame of the 5'-MLL/KIAA0128-3' mRNA fusion allows for the formation of a novel chimeric protein. Septin 6 is the third member of the Septins that is fused to the MLL protein; the other two are hCDCrel at 22q11 and MSF at 17q25.
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PMID:An ins(X;11)(q24;q23) fuses the MLL and the Septin 6/KIAA0128 gene in an infant with AML-M2. 1147 64

Diphtheria fusion proteins are a novel class of agents for the treatment of chemotherapy resistant AML. We prepared DT(388)IL3 composed of human interleukin-3 (IL3) fused to the catalytic and translocation domain of diphtheria toxin (DT(388)) and assessed its activity on patient AML blasts. The number and affinity of IL3 receptors in circulating blasts was measured using a radiolabeled IL3 agonist (SC-65461). Ninety-two percent of patients' blasts had both high and low affinity IL3 receptors. DT(388)IL3 cytotoxicity (>1 log cell kill) was seen in nine of 25 samples (36%). There was a significant correlation between DT(388)IL3 log cell kill and blast high affinity IL3 receptor density (P=0.0044). These results show that specific high affinity IL3 binding is one factor important in the sensitivity of patients' leukemic blasts to DT(388)IL3.
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PMID:High affinity interleukin-3 receptor expression on blasts from patients with acute myelogenous leukemia correlates with cytotoxicity of a diphtheria toxin/IL-3 fusion protein. 1153 21


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