Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A patient with acute monocytic leukemia (AMoL) and t(6;11)(q27;q23) developed acute lymphoblastic leukemia (ALL) and t(4;11)(q21;23), 10 months after complete remission of the AMoL. The MLL gene, normally located at band 11q23, appeared differently rearranged in the cells of these two leukemias, showing a different origin for the two malignant clones. The responsibility of etoposide, used in treatment of the AML, in the occurrence of the ALL is probable in this patient.
Leukemia 1994 Dec
PMID:Distinct MLL gene rearrangements associated with successive acute monocytic and lymphoblastic leukemias in the same patient. 780 11

Translocations involving chromosomal band 11q23 are associated with leukemias. These translocations fuse the MLL, a gene with sequence homology to the Drosophila trithorax, to genes from a number of other chromosomal loci. We have characterized two t(1;11)(q21;q23) translocations that fuse the MLL gene to a novel gene, AF1q on chromosomal band 1q21, in two infants with acute myelomonocytic leukemia (AMMOL). In one of these patients, der(11) represents an inframe fusion of the N-terminal portion of MLL gene to the complete AF1q open reading frame, whereas der(1) does not give rise to an open reading frame. This observation suggests that the N-terminal portion of MLL gene is critical for leukemogenesis in translocations involving band 11q23. The predicted wild-type AF-1q product is a 9-kD protein with no similarity to any other protein in the data banks. The AF1q mRNA is highly expressed in the thymus but not in peripheral lymphoid tissues. In contrast to its restricted distribution in normal hematopoietic tissue, AF1q was expressed in all leukemic cell lines tested.
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PMID:A novel gene, AF1q, fused to MLL in t(1;11) (q21;q23), is specifically expressed in leukemic and immature hematopoietic cells. 783 68

A nested polymerase chain reaction (PCR) protocol was developed for rapid detection of four different 11q23 abnormalities by a single PCR assay. During each of the two PCR rounds a sense primer located within exon 5 of the MLL gene at 11q23 was combined with four different antisense primers, each located within possible translocation partner genes at chromosomes 4, 6, 9, and 19, respectively. Except for the MLL primer all primers used during the second round of nested-PCR carried a characteristic fluorescence label at their 5'-end. Agarose gel analysis of the PCR products was sufficient to discriminate between the absence of any of the four MLL rearrangements and the presence of at least one of them. Discrimination of the four different MLL translocation partner genes was not possible by agarose gel analysis due to a molecular heterogeneity of the 11q23 breakpoints resulting in PCR products of variable size. For this reason, automatic fluorescence-based DNA-fragment analysis was used to exactly define the MLL translocation partner genes if a positive result had been obtained by agarose gel analysis. In patients with leukemia, this assay may enable a fast and highly sensitive detection of different 11q23 abnormalities, which usually correlate with poor clinical prognosis.
Leukemia 1995 Jan
PMID:Detection of four different 11q23 chromosomal abnormalities by multiplex-PCR and fluorescence-based automatic DNA-fragment analysis. 784 20

We and others have recently reported a high frequency (70-80%) of ALL-1 (MLL, HRX, HTRX) gene rearrangements in infants with acute leukemias (AL) aged less than 1 year. Preliminary observations in limited series also suggested that ALL-1 gene configuration is an important prognostic factor in this leukemic subset. We have now extended our study to a series of 45 AL patients aged between 0 and 18 months. The genomic configuration of ALL-1 in leukemic DNAs was determined by Southern blot hybridization and correlated with biological and clinical features at presentation, as well as with treatment outcome. Twenty-nine out of 45 (64%) patients showed ALL-1 rearrangements, including 4/11 (36%) infants aged between 13 and 18 months. Considering morphological types, 24/38 cases with acute lymphoblastic leukemia and 5/7 patients with acute myeloid leukemia showed ALL-1 rearrangements. The features more frequently found in association with ALL-1 rearrangements were hyperleukocytosis (P < 0.007) and CD19+/CD10- blast immunophenotype (P < 0.02). ALL-1 status was an independent prognostic marker of event-free survival (EFS) in a multivariate model including age, sex and WBC count, and maintained its statistical significance when FAB morphology was considered in the analysis by including AML patients. Considering the ALL cases the actuarial EFS was 57 and 9% for infants with germline and rearranged ALL-1 configuration, respectively (P = 0.008). A high frequency of ALL-1 gene alterations in infant AL is confirmed by this study. In addition, our results emphasize the need for extending the analysis of ALL-1 gene status to infants with AL aged > 12 months. We show that this genetic lesion is the most important variable negatively affecting prognosis in a multivariate model including other known risk factors. This latter observation should influence the choice of risk-adapted treatment strategies in this AL subset.
Leukemia 1995 Mar
PMID:Prognostic relevance of ALL-1 gene rearrangement in infant acute leukemias. 788 37

Translocations involving chromosome band 11q23, found in acute lymphoid and myeloid leukemias, disrupt the MLL gene. This gene encodes a putative transcription factor with homology to the zinc fingers and other domains of the Drosophila trithorax gene product and to the "AT-hook" motif of high mobility group proteins. To map potential transcriptional activation or repression domains of the MLL protein, yeast GAL4 DNA-binding domain and MLL hybrid protein-expressing plasmids were cotransfected with chloramphenicol acetyltransferase reporter plasmids in a transient transfection system. We found that MLL contains a strong activation domain and a repression domain. The former, located telomeric (3') to the breakpoint region, activated transcription 18-fold to > 200-fold, depending on the promoter and cell line used for transfection. A repression domain that repressed transcription 4-fold was located centromeric (5') to the breakpoint region of MLL. The MLL AT-hook domain protein was expressed in bacteria and was utilized in a gel mobility shift assay to assess DNA-binding activity. The MLL AT-hook domain could bind cruciform DNA, recognizing structure rather than sequence of the target DNA. In translocations involving MLL, loss of an activation domain with retention of a repression domain and a DNA-binding domain on the der(11) chromosome could alter the expression of downstream target genes, suggesting a potential mechanism of action for MLL in leukemia.
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PMID:11q23 translocations split the "AT-hook" cruciform DNA-binding region and the transcriptional repression domain from the activation domain of the mixed-lineage leukemia (MLL) gene. 793

A patient with secondary acute myelomonocytic leukemia after treatment with chronic oral etoposide (VP-16) for lung cancer is reported. The leukemic cells showed a t(9;11)(p22;q23) translocation. Southern blot analysis revealed the rearrangement of the MLL (ALL-1/HRX) gene at 11q23. Reverse transcriptase-polymerase chain reaction (RT-PCR) revealed a chimeric mRNA between the MLL gene at 11q23 and LTG9 (MLLT3/AF-9) gene at 9p22. The patient was successfully treated with a VP-16 based regimen. This case is instructive in the understanding of the leukemogenesis of VP-16-related leukemias.
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PMID:Acute myelomonocytic leukemia after treatment with chronic oral etoposide: are MLL and LTG9 genes targets for etoposide? 794 64

Specific structural rearrangements involving chromosome band 11q23 occur in a variety of hematologic malignancies, including an estimated 2-7% of patients with acute lymphoblastic leukemia (ALL). Translocations involving chromosome band 11q23 have been associated with a poor prognosis in patients with ALL. Recently, a gene known as MLL has been identified which is involved in acute lymphoid and myeloid leukemias with rearrangements at 11q23. A 0.74-kilobase (kb) cDNA probe from the MLL gene can detect both common and uncommon rearrangements involving MLL on conventional Southern blots. We studied 86 newly diagnosed adults entered on an ALL clinical trial to investigate the incidence of MLL gene rearrangements and to determine clinical, morphologic, immunologic and cytogenetic characteristics of such patients. Two of 86 patients had MLL gene rearrangements detected by Southern blot analysis. One of these 86 patients had an 11q23 translocation by cytogenetic analysis whereas the second patient was unevaluable by standard cytogenetic analysis. Southern blot identification of rearrangements involving MLL, especially in patients with limited material for cytogenetic analysis, can provide critical diagnostic and prognostic information which may be useful in the clinical management of patients with these abnormalities.
Leukemia 1994 Nov
PMID:Detection of MLL gene rearrangements in adult acute lymphoblastic leukemia. A Cancer and Leukemia Group B study. 796 37

To characterize the functions of MLL fusion transcripts, we cloned the gene that fuses to MLL in the translocation t(11;19)(q23;p13.1). This translocation is distinct from another type of 11;19 translocation with a 19p13.3 breakpoint that results in the fusion of MLL to the ENL gene. By PCR screening of a cDNA library prepared from a patient's leukemia cells with this translocation, we obtained a fusion transcript containing exon 7 of MLL and sequence of an unknown gene. The sequence of this gene was amplified and used as a probe to screen a fetal brain cDNA library. On Northern blot analysis, this cDNA detected a 4.4-kb transcript that was abundant in peripheral blood leukocytes, skeletal muscle, placenta, and testis and expressed at lower levels in spleen, thymus, heart, brain, lung, kidney, liver, and ovary. In addition, a 2.8-kb transcript was present in peripheral blood, testis, and placenta. On "zoo blots," this gene was shown to be evolutionarily conserved in 10 mammalian species as well as in chicken, frog, and fish. We have named this gene ELL (for eleven-nineteen lysine-rich leukemia gene). A highly basic, lysine-rich motif of the predicted ELL protein is homologous to similar regions of several proteins, including the DNA-binding domain of poly(ADP-ribose) polymerase. The characterization of the normal functions of ELL as well as its altered function when fused to MLL will be critical to further our understanding of the mechanisms of leukemogenesis.
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PMID:Cloning of ELL, a gene that fuses to MLL in a t(11;19)(q23;p13.1) in acute myeloid leukemia. 799 93

Rearrangements involving chromosome band 11q23 are very common in acute leukaemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from translocation breakpoints, the great majority of translocations involve the MLL (myeloid-lymphoid leukaemia) gene. The MLL gene has several different names, ALL1, Htrx, HRX; the central part of the gene codes for multiple zinc fingers which show strong homology to the Drosophila trithorax gene. MLL is involved in four common translocations as well as in 25 uncommon or rare translocations, insertions and deletions. The translocation breakpoints occur within an 8.3 kb region which can be detected with a 0.74 kb cDNA probe. Twenty-five percent of patients have a deletion 3' of the breakpoint which includes the zinc finger region. Patients who previously received drugs that inhibit topoisomerase II often develop acute leukaemia with translocations involving 11q23. These translocations break MLL in the same 8.3 kb region. In the three breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimaeric transcript, consisting of 5' MLL and the 3' segment of the other gene. Although transcripts were also cloned from the other derivative chromosome, all the evidence indicates that the critical fusion gene is on the derivative 11 chromosome. The molecular dissection of these rearrangements will provide insights into the biology of MLL and into the interaction of MLL with topoisomerase II inhibitors. In addition, this research has provided DNA probes that will be important for diagnosis and for monitoring patients during the course of their disease.
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PMID:Rearrangements involving chromosome band 11Q23 in acute leukaemia. 814 23

We examined ten cases of acute lymphoblastic leukemia (ALL) in infants (less than 1 year of age) by RT-nested PCR for a MLL-1/AF4 rearrangement. Five patients revealed a positive result. The specific PCR product differed in size from approximately 380-670 bp indicating various splicing variants in the MLL-1/AF4 rearrangement. Three patients had a fusion between exon 6 of the MLL-1 gene and codon 362 of the known AF4 cDNA sequence. Moreover, in two patients more than one specific PCR product was detected, possibly due to alternative splicing. In the first case, sequencing of these products revealed a hybrid mRNA consisting of MLI-1 exon 7 or exon 8, respectively, fused to the AF4 gene at codon 348. In the second case with alternative splicing, again, exon 7 or 8 of the MLL-1 gene were fused to the AF4 gene as in case 1. The AF4 sequence involved in this patient, however, started at codon 362. The AF4 break was, therefore, identical to the three MLL-1/AF4 positive patients as described above. Moreover, we investigated all ten patients for the reciprocal mRNA transcript AF4/MLL-1 by a similar PCR approach. In none of these patients, including the five MLL-1/AF4 positive cases was a specific PCR product obtained. However, in the MV411 cell line bearing a t(4;11), which served as a positive control in our MLL-1/AF4-PCR assay, the reciprocal AF4/MLL-1 mRNA was detected. Our results indicate that a MLL-1/AF4 rearrangement occurs in about 50% of infants with ALL. In contrast, the reciprocal hybrid mRNA can only rarely be detected, if at all.
Leukemia 1994 Apr
PMID:Molecular analysis of MLL-1/AF4 recombination in infant acute lymphoblastic leukemia. 815 49


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