UMLS:C0598766 - FACTA Search

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Query: UMLS:C0598766 (leukemogenesis)
4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Partial-tandem duplication (PTD) of an internal portion of MLL occurs in some cases of acute myelogenous leukemia (AML) with trisomy 11 or a normal karyotype. This type of MLL rearrangement may be transcribed into an mRNA species that is capable of encoding a partially duplicated protein associated with leukemogenesis. However, although several kinds of oncogenes, especially MYC, are often amplified on double-minute chromosomes (dmins) in hematological malignancies, no amplification of MLL has been reported in AML. Here, we report the first documented case of a patient with AML whose leukemic cells exhibited amplification of MLL on dmins. Furthermore, in this patient, MLL was rearranged in a PTD manner, with in-frame fusion of exons 2 and 6.
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PMID:Amplification on double-minute chromosomes and partial-tandem duplication of the MLL gene in leukemic cells of a patient with acute myelogenous leukemia. 979 May 9

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

The MLL (HRX/ALL-1 gene is frequently disrupted in infantile leukemias and therapy-related leukemias and fused to various translocation partner genes. We previously showed that chimeric MLL proteins localize in the nuclei in a fashion similar to that of MLL protein even if the partner gene encodes a cytoplasmic protein and indicated the importance of the N-terminal portion of MLL common to various MLL translocations. This time we established an inducible expression system for chimeric MLL-LTG9 and truncated N-terminal MLL proteins (MLL-Zf(-)) in 32Dcl3 cells. By utilizing this system, we were able to show inhibition of Hox a7, Hox b7 and Hox c9 genes' expression by induced MLL-LTG9 and MLL-Zf(-). Up-regulation of Hox a7, Hox b7 and Hox c9 was observed when 32Dcl3 cells were cultured with granulocyte colony stimulating factor (G-CSF) in place of interleukin 3 and induction of MLL-LTG9 and MLL-Zf(-) was shown to suppress this upregulation. At the same time, expression of two mammalian Polycomb group genes, M33 and mel-18, which both reportedly affect Hox genes' expression, was not inhibited by MLL-LTG9 and MLL-Zf(-) induction. These results indicate that MLL has an important effect on the expression of at least some Hox genes in hematopoietic cells and suggest that inhibition of the proper expression of Hox genes by chimeric MLL proteins may dysregulate hematopoietic cell differentiation and proliferation, which then can lead to leukemogenesis.
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PMID:Establishment of an inducible expression system of chimeric MLL-LTG9 protein and inhibition of Hox a7, Hox b7 and Hox c9 expression by MLL-LTG9 in 32Dcl3 cells. 1002 90

Rearrangements involving the MLL gene at chromosome 11q23 are associated with leukemia and are present in up to 70% of infant leukemias. Loss of heterozygosity (LOH) has been shown for anonymous polymorphic markers at 11q23 in adult leukemias. To study LOH at the MLL locus, we have identified two new polymorphic microsatellite markers: a GAA repeat (mllGAAn) in intron 6 of the MLL gene and a GA (mllGAn) repeat in the 5' flanking region of the gene, approximately 2 kb upstream of the translation initiation codon. The heterozygosity index of mllGAAn is 0.54, which renders it useful for analyzing LOH. We screened two groups of leukemia patients to study LOH at the mllGAAn marker. Group A (n = 18) was selected on the basis of presentation before 18 months. Cytogenetic and reverse transcription-polymerase chain reaction analysis showed that 9 of these 18 children had translocations involving MLL. No LOH was observed. Group B (n = 36) were randomly selected children who had presented with leukemia between 1993 and 1994. Cytogenetic analysis of this group showed a variety of different chromosomal abnormalities. LOH was shown in 9 of 20 individuals (45%) who were informative. Microsatellite instability (MSI) was demonstrated in 1 of 18 individuals in group A and 5 of 36 individuals (13.9%) in group B. MSI and LOH were observed simultaneously in three individuals. Loss of an allele was confirmed in one individual by fluorescence in situ hybridization. Individuals with MSI or LOH at mllGAAn were selected for analysis at anonymous polymorphic markers D11S1364 and D11S1356, which flank the MLL gene. No LOH or MSI was observed at these markers in those individuals who were informative. These results show that LOH at the MLL gene locus is a common event during leukemogenesis. Furthermore, the presence of MSI at this locus suggests that the region is a hotspot for genetic instability.
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PMID:Loss of heterozygosity and microsatellite instability at the MLL locus are common in childhood acute leukemia, but not in infant acute leukemia. 1273 3

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

One of the most common chromosomal abnormalities in acute leukemia is a reciprocal translocation involving the HRX gene (also called MLL, ALL-1, or HTRX) at chromosomal locus 11q23, resulting in the formation of HRX fusion proteins. Using the yeast two-hybrid system and human cell culture coimmunoprecipitation experiments, we show here that HRX proteins interact directly with the GADD34 protein. We have found that transfected cells overexpressing GADD34 display a significant increase in apoptosis after treatment with ionizing radiation, indicating that GADD34 expression not only correlates with apoptosis but also can enhance apoptosis. The amino-terminal third of the GADD34 protein was necessary for this observed increase in apoptosis. Furthermore, coexpression of three different HRX fusion proteins (HRX-ENL, HRX-AF9, and HRX-ELL) had an anti-apoptotic effect, abrogating GADD34-induced apoptosis. In contrast, expression of wild-type HRX gave rise to an increase in apoptosis. The difference observed here between wild-type HRX and the leukemic HRX fusion proteins suggests that inhibition of GADD34-mediated apoptosis may be important to leukemogenesis. We also show here that GADD34 binds the human SNF5/INI1 protein, a member of the SNF/SWI complex that can remodel chromatin and activate transcription. These studies demonstrate, for the first time, a gain of function for leukemic HRX fusion proteins compared to wild-type protein. We propose that the role of HRX fusion proteins as negative regulators of post-DNA-damage-induced apoptosis is important to leukemia progression.
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PMID:Leukemic HRX fusion proteins inhibit GADD34-induced apoptosis and associate with the GADD34 and hSNF5/INI1 proteins. 1049 Jun 42

Translocations affecting the chromosomal locus 11q23 are hallmarks of infant leukemias. These events disrupt the MLL gene (also ALL-1 or HRX) and fuse the MLL amino terminus in frame with a variety of unrelated proteins. The ENL gene on 19p13.1 is a recurrent fusion partner of MLL. Whereas potential functions have been suggested for isolated domains of either MLL or ENL no experimental data exist for the biological properties of the complete chimeric MLL-ENL protein. We show here that the fusion of MLL with ENL creates a novel molecule that is a potent general transcriptional transactivator in transient reporter gene assays. MLL-ENL strongly transactivated several unrelated promoters including the promoter of Hoxa7 a potential target gene for the unaltered MLL protein. This transactivation capability was cell type specific and it was critically dependent on the contributions of the methyltransferase-homology (MT) region of MLL in combination with the C-terminus of ENL. Squelching experiments and gel retardation studies identified the ENL C-terminus as a binding partner for an unknown factor and the MLL MT region as a unique general DNA binding motif. The potential implications of these findings for the leukemogenesis by MLL-ENL are discussed.
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PMID:The leukemogenic fusion of MLL with ENL creates a novel transcriptional transactivator. 1051 53

The frequency of leukemia and myelodysplasia following treatment with cytotoxic agents is increasing. Theses treatment-related leukemias raise both theoretical and practical concerns. On a theoretical basis, cytogenetic and molecular abnormalities described constitute useful models to study leukemogenesis. On a practical basis, prognosis of treatment related-leukemia is somehow unfavorable and implies to take in account this risk in the development of combination therapy for solid tumors or hematological malignancies. There are two distinctive types of treatment-induced leukemia: those secondary after alkylating agents and those secondary after topoisomerase-II- inhibitors. These two types of leukemia after regarding their clinical and their hematological characteristics, but also regarding their prognosis and their associated molecular abnormalities. Leukemias induced by alkylating agents occur generally 5 or 6 years after the beginning of the chemotherapy and are preceded by a more or less long phase of pancytopenia or myelodysplasia and according to their cytologic aspects are difficult to be classified within FAB classification. Their prognosis is pejorative. The most commonly found cytogenetic abnormalities associated with these types of induced leukemia are losses or deletions of chromosomes 5 and 7. Leukemias induced by topoisomerase-II-inhibitors occur shortly after the treatment (12 to 30 months), they begin generally suddenly without preleukemia prodom and their more frequent cytological aspects are M4 and M5 type. The prognosis is less severe than alkylating agent related forms with higher response rates and is dependant of discovered cytogenetic abnormalities. The more frequent molecular abnormalities are not chromosome deletions but balanced translocations. They affect particularly the MLL gene located at band 11q23. Other translocations have been described in this type of leukemia and are comparable to the one found in the de novo leukemia (t8;21, t15;17) for example. The evaluation of the risk of treatment-related leukemia for a given chemotherapeutic agent is difficult as for as current treatment use the combination of several agents potentially leukemogenic (chemotherapy and radiotherapy, combination chemotherapy). It is necessary to set up an up-dated data register in order to centralize all therapy-related myelodysplasia and leukemia within the treatment of a given type of cancer.
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PMID:[Leukemias induced by anticancer chemotherapies]. 1058 9

The t(10;11)(p12-p13;q14-q21) observed in a subset of patients with either acute lymphoblastic leukemia or acute myeloid leukemia has been shown to result in the fusion of AF10 on chromosome 10 with CALM (also named CLTH) on chromosome 11. AF10 was originally identified as a fusion partner of MLL in the t(10;11)(p12-p13;q23) observed in myeloid leukemia. CALM is a newly isolated gene, cloned as the fusion partner of AF10 in the monocytoid cell line, U937. In order to understand the relationship between MLL, AF10, CALM and the leukemic process, fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction were used to study a series of nine leukemia patients with a t(10;11). Six had myeloid leukemia (AML-M0, AML-M1, AML-M4 and AML-M5) and three had T cell lymphoblastic leukemia. We identified four different CALM/AF10 fusion products in five patients and AF10/CALM reciprocal message in one. We conclude that fusion of CALM and AF10 is a recurring abnormality in both lymphoid and myeloid leukemias of various types including AML-M5, and that the breakpoints in the two types of leukemia do not differ. Our data indicate that the CALM/AF10 fusion product on the der(10) chromosome is critical to leukemogenesis. Leukemia (2000) 14, 100-104.
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PMID:Identification and molecular characterization of CALM/AF10fusion products in T cell acute lymphoblastic leukemia and acute myeloid leukemia. 1063 83

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