Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A chromosomal translocation, t(4;11)-(q21;q23), is associated with an aggressive mixed-lineage leukemia. A yeast artificial chromosome was used to clone the chromosomal breakpoint of this translocation in the RS4;11 cell line. The breakpoint sequences revealed an inverted repeat bordered by a consensus site for topoisomerase II binding and cleavage as well as chi-like elements. The der(11) chromosome encodes a fusion RNA and predicted chimeric protein between the 11q23 gene MLL and a 4q21 gene designated AF4. The sequence of the complete open reading frame for this fusion transcript reveals the MLL protein to have homology with DNA methyltransferase, the Drosophila trithorax gene product, and the "AT-hook" motif of high-mobility-group proteins. An alternative splice that deletes the AT-hook region of MLL was identified. AF4 is a serine- and proline-rich putative transcription factor with a glutamine-rich carboxyl terminus. The composition of the complete MLL-AF4 fusion product argues that it may act through either a gain-of-function or a dominant negative mechanism in leukemogenesis.
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PMID:Acute mixed-lineage leukemia t(4;11)(q21;q23) generates an MLL-AF4 fusion product. 768 31

The MLL gene, on human chromosome 11q23, undergoes chromosomal translocation in acute leukemias, resulting in gene fusion with AF4 (chromosome 4) and ENL (chromosome 19). We report here translocation of MLL with nine different chromosomes and two paracentric chromosome 11 deletions in early B cell, B- or T-cell lineage, or nonlymphocytic acute leukemias. The mRNA translocation junction from 22 t(4;11) patients, including six adult leukemias, and nine t(11;19) tumors reveals a remarkable conservation of breakpoints within MLL, AF4, or ENL genes, irrespective of tumor phenotype. Typically, the breakpoints are upstream of the zinc-finger region of MLL, and deletion of this region can accompany translocation, supporting the der(11) chromosome as the important component in leukemogenesis. Partial sequence of a fusion between MLL and the AFX1 gene from chromosome X shows the latter to be rich in Ser/Pro codons, like the ENL mRNA. These data suggest that the heterogeneous 11q23 abnormalities might cause attachment of Ser/Pro-rich segments to the NH2 terminus of MLL, lacking the zinc-finger region, and that translocations occur in early hematopoietic cells, before commitment to distinct lineages.
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PMID:Acute leukemias of different lineages have similar MLL gene fusions encoding related chimeric proteins resulting from chromosomal translocation. 837 28

11q23 chromosome aberrations are frequently observed in infantile as well as therapy-related leukemias. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partner genes such as AF4/FEL, LTG9/AF9 and LTG19/ENL. The resulting chimeric mRNAs are fused in frame and have been predicted to encode leukemia-specific chimeric proteins. In the present study, we raised antibodies against MLL, LTG9 and LTG19 and demonstrated that MLL and chimeric MLL-LTG9 and MLL-LTG19 products are synthesized in vivo and are localized in the nuclei, using immunofluorescence and cell fractionation studies. The truncated N-terminal portion of the MLL product common to the various types of 11q23 translocation was also localized in the nuclei in a similar fashion. Murine 32Dc13 cells stably expressing the truncated N-terminal MLL protein exhibited an inhibition of differentiation and a growth advantage following stimulation by granulocyte-colony stimulating factor, although the IL-3 dependency was not significantly changed in comparison to the parental cells. These results suggest that the N-terminal portion common to various MLL-chimeric products plays an important role in leukemogenesis.
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PMID:Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation. 893 41

In infantile leukemias and therapy-related leukemias, the MLL gene is frequently found to be disrupted and fused to various translocation partner genes, such as AF4/FEL, LTG9/AF9 and LTG19/ENL as a result of 11q23 translocations. We previously showed that the N-terminal portion common to various chimeric MLL products, as well as to MLL-LTG9 and MLL-LTG19, localizes in the nuclei, and therefore suggested that it might play an important role in leukemogenesis. In the present study, MLL-AF6 chimeric products found in the t(6;11)(q27;q23) translocation were analysed since AF6, a Ras-binding protein, exhibits a different subcellular localization from that of LTG9/AF9 and LTG19/ENL. Immunofluorescence staining data and cell fractionation analyses demonstrated that MLL-AF6 chimeric products localize in the nuclei despite the fact that AF6 itself localizes in the cytoplasm, confirming the importance of the nuclear localization of chimeric MLL products. The region in the N-terminal portion of MLL responsible for this nuclear localization was examined and found to be a region containing AT-hook motifs.
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PMID:Chimeric MLL products with a Ras binding cytoplasmic protein AF6 involved in t(6;11) (q27;q23) leukemia localize in the nucleus. 934 1

AF4 is the 4q21 gene involved in the acute lymphoblastic leukemia associated t(4;11)(q21;q23) where it forms a fusion gene with MLL. In order to gain insight into AF4's role in leukemogenesis we have studied its functional domains and expression pattern during murine development. We have cloned the murine homolog, Af4. We have demonstrated that 5' half of Af4 encodes a region with transcriptional transactivation activity which is disrupted by the t(4;11) in human leukemias. We have also localized the murine AF4 protein to the nucleus supporting a role for AF4 in transcription. The developmental expression pattern of Af4 was determined in situ hybridization and suggests Af4 plays an important role in the development of the hematopoietic, cardiovascular, skeletal and central nervous systems. A repeating pattern of Af4 expression in development is down-regulation with differentiation of a tissue. Among the cell types where this pattern of down-regulation is noted are B-lymphocytes. These findings raise the possibility that the disruption of normal AF4 function by the translocation may contribute to leukemogenesis.
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PMID:Cloning and developmental expression of the murine homolog of the acute leukemia proto-oncogene AF4. 936 43

Acute leukemia with t(4;11)(q21,q23) translocation results from the in-frame fusion of the MLL to the AF4/FEL gene. In previous studies, we and others demonstrated that AF4 transcripts are present in a variety of hematopoietic and nonhematopoietic human cells. To further study the wild-type and leukemia fusion AF4, we used glutathione S-transferase (GST)-fusion proteins as immunogens to produce rabbit polyclonal antibodies that were specific for normal and chimeric AF4 proteins. Using Western blotting analysis, we demonstrated that the AF4 gene encodes proteins with apparent molecular weight of 125 and 145 kD. A 45-kD protein coprecipitated with AF4 protein in immunoprecipitation. Also, the anticipated MLL-AF4-encoded 240-kD protein was detected in all cell lines with t(4;11) translocations; fusion proteins were present in lesser quantity than the wild-type AF4. The proteins recognized by the antibodies are of the predicted sizes of the AF4 and MLL-AF4-encoded proteins based on previous DNA sequencing analysis. The MLL-AF4 fusion protein had a similar subcellular distribution as AF4. Both t(4;11) and non-t(4;11) leukemic cells showed a similar pattern of punctate nuclear staining in all cell lines tested using confocal immunofluorescence microscopy. AF4 antibodies should be useful for further elucidation of the function of AF4 in normal cellular physiology, as well as the function of MLL-AF4 in leukemogenesis. The antibodies should also be helpful for the diagnosis of the MLL-AF4 fusion proteins in t(4;11) leukemias.
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PMID:AF4 encodes a ubiquitous protein that in both native and MLL-AF4 fusion types localizes to subnuclear compartments. 980 77

Ikaros, a zinc finger-containing DNA-binding protein, is required for normal lymphocyte development, and germline mutant mice that express only non-DNA binding dominant-negative "leukemogenic" Ikaros isoforms lacking critical N-terminal zinc fingers develop an aggressive form of lymphoblastic leukemia 3-6 months after birth. Therefore, we sought to determine whether molecular abnormalities involving the Ikaros gene could contribute to the development of acute lymphoblastic leukemia (ALL) in infants. Primary leukemic cells were freshly obtained from 12 infants (<1 year of age) with newly diagnosed ALL. In leukemic cells from each of the 12 infants with ALL, we found high level expression of dominant-negative isoforms of Ikaros with abnormal subcellular compartmentalization patterns. PCR cloning and nucleotide sequencing were used to identify the specific Ikaros isoforms and detect Ikaros gene mutations in these cells. Leukemic cells from seven of seven infants with ALL, including five of five MLL-AF4(+) infants, expressed dominant-negative Ikaros isoforms Ik-4, Ik-7, and Ik-8 that lack critical N-terminal zinc fingers. In six of seven patients, we detected a specific mutation leading to an in-frame deletion of 10 amino acids (Delta KSSMPQKFLG) upstream of the transcription activation domain adjacent to the C-terminal zinc fingers of Ik-2, Ik-4, Ik-7, and Ik-8. In contrast, only wild-type Ik-1 and Ik-2 isoforms with normal nuclear localization were found in normal infant bone marrow cells and infant thymocytes. These results implicate the expression of dominant-negative Ikaros isoforms and the disruption of normal Ikaros function in the leukemogenesis of ALL in infants.
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PMID:Expression of dominant-negative and mutant isoforms of the antileukemic transcription factor Ikaros in infant acute lymphoblastic leukemia. 989 93

Some chromosomal translocations in acute leukemias involve the fusion of the trithorax-related protein Mll (also called HRX, All1, Htrx,) with a variety of heterologous proteins. In acute lymphoblastic leukemia associated with the t(4;11)(q21;q23) translocation, the 4q21 gene that fuses with Mll is AF4. To gain insight into the potential role of AF4 in leukemogenesis and development, this gene was inactivated by homologous recombination in mice. As expected from the tissue distribution of the AF4 transcript, development of both B and T cells is affected in AF4 mutant mice. A severe reduction of the thymic double positive CD4/CD8 (CD4(+)/CD8(+)) population was observed; in addition most double- and single-positive cells expressed lower levels of CD4 and CD8 coreceptors. Most importantly, the reconstitution of the double-positive compartment by expansion of the double-negative cell compartment was severely impaired in these mutant mice. In the bone marrow pre-B and mature B-cell numbers are reduced. These results demonstrate that the function of the mAF4 gene is critical for normal lymphocyte development. This raises the possibility that the disruption of the normal AF4 gene or its association with Mll function by translocation may orient the oncogenic process toward the lymphoid lineage. This represents the first functional study using a knock-out strategy on one of the Mll partner genes in translocation-associated leukemias. (Blood. 2000;96:705-710)
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PMID:Altered lymphoid development in mice deficient for the mAF4 proto-oncogene. 1088 38

Somatically acquired genetic alterations play an important role in the pathogenesis of acute lymphoblastic leukemia. The molecular analysis of these alterations has increased our understanding of the mechanisms of leukemogenesis. In addition, this information has led to improvements in our abilities to predict treatment response and to deliver the optimal intensity of treatment to individual patients. For example, the prognosis for patients with acute lymphoblastic leukemia whose leukemic cells express the TEL-AML1 fusion is favorable when they are treated on modem chemotherapy protocols, whereas patients whose leukemic lymphoblasts contain the MLL-AF4 or the BCR-ABL fusion sometimes require allogeneic hematopoietic stem cell transplantation for cure. Molecular techniques are also used to detect minimal residual disease and genetic polymorphisms that are important in optimizing drug therapy.
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PMID:Molecular diagnostics in the treatment of childhood acute lymphoblastic leukemia. 1103 50

The t(4;11) translocation is the cytogenetic hallmark of a subset of acute lymphoblastic leukemias characterized by pro-B immunophenotype and a dismal prognosis. This translocation fuses the MLL gene on chromosome band 11q23 and the AF4 gene on 4q21, resulting in the expression of fusion transcripts from both translocated chromosomes. The MLL-AF4 chimeric transcript is thought to mediate the leukemic transformation. The MLL genomic disruption detected by Southern blot and the RT-PCR for the MLL-AF4 chimeric transcript expression are molecular evidence of this chromosomal translocation. However, similar molecular rearrangements have also been identified in cases without the cytogenetic t(4;11). We report a 30-year-old patient with high risk ALL, a normal karyotype, and molecular evidence of MLL-AF4 fusion. Using a double color FISH assay with MLL specific PAC probes, a cryptic t(4;11) due to insertion of 5' MLL sequences in chromosome 4q21 was demonstrated. Consequently the MLL-AF4 was encoded by der(4). This insertion mechanism precludes the genomic recombination of AF4-MLL and supports the crucial role played by MLL-AF4 in leukemogenesis. The findings of our case, along with others, show the importance of complementing the karyotype with molecular and FISH techniques.
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PMID:Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4. 1136 62


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