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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This manuscript reports the differential expression of the AF4 gene among human tissues. AF4 mRNA is highly expressed in normal placental tissue which correlates with the newborn age of patients presenting with leukemia characterized by the MLL/AF4 gene rearrangement.
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PMID:Differential expression of AF4/FEL mRNA in human tissues. 867 40

We prospectively analyzed p15 and p16 promoter methylation patterns using methylation-specific polymerase chain reaction (PCR) in patients with adult and childhood acute leukemias and studied the association of methylation patterns with chromosomal abnormalities and prognostic variables. In nearly all French-American-British leukemia subtypes, we found p15 methylation in bone marrow or peripheral blood cells from 58% (46/79) of patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or acute biphenotypic leukemia (ABL). An identical alteration was detected in blood plasma from 11 of 12 of these patients (92%). We also demonstrated for the first time concomitant p16 and p15 methylation in 22% (8/37) of adults with AML or ALL, exclusively in those with M2, M4, or L2 subtypes. According to cytogenetic data from 35 patients with ALL, AML, or ABL, 82% (14/17) of those with unmethylated p15 alleles had normal karyotypes or hyperdiploidies associated with a favorable prognosis. Conversely, 44% (8/18) of patients with p15 methylation had chromosomal translocations, inversions, or deletions, suggesting an interplay of these abnormalities with p15 methylation. As a prognostic marker for disease monitoring, p15 methylation appears to be more widely applicable than BCR-ABL, AF4-MLL, and AML1-ETO transcripts, which were detectable in only 8% (4/48) of patients by reverse transcriptase-PCR. Thirty-nine of 43 blood samples (91%) sequentially collected from 12 patients with AML, ALL, or ABL showed p15 methylation status in excellent concordance with morphologic disease stage. Early detection of p15 methylation at apparent remission or its acquisition during follow-up may prove valuable for predicting relapse. Overall survival of patients with p15 methylation was notably shortened among 38 adults with AML and 12 adults with ALL. Aberrant p15 methylation may have important prognostic implications for clinical monitoring and risk assessment. (Blood. 2000;95:1942-1949)
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PMID:Aberrant p15 promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. 1104 32

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.
Leukemia 2001 Apr
PMID:Cryptic t(4;11) encoding MLL-AF4 due to insertion of 5' MLL sequences in chromosome 4. 1136 62

The MLL gene in chromosome band 11q23 is frequently rearranged in acute lymphoblastic and acute myeloid leukemias. To date, more than 50 different chromosomal regions are known to participate in translocations involving 11q23, many of which affect MLL. The pathogenetically important outcome of these rearrangements is most likely the creation of a fusion gene consisting of the 5' part of the MLL gene and the 3' end of the partner gene. Although abnormalities of the MLL gene as such are generally associated with poor survival, recent data suggest that the prognostic impact varies among the different fusion genes generated. Hence, detection of the specific chimeric gene produced is important for proper prognostication and clinical decision making. We have developed a paired multiplex reverse-transcriptase polymerase chain reaction analysis to facilitate a rapid and accurate detection of the most frequent MLL fusion genes in adult and childhood acute leukemias. To increase the specificity, two sets of primers were designed for each fusion gene, and these paired primer sets were run in parallel in two separate multiplex one-step PCR reactions. Using the described protocol, we were able to amplify successfully, in one single assay, the six clinically relevant fusion genes generated by the t(4;11)(q21;q23) [MLL/AF4], t(6;11)(q27;q23) [MLL/AF6], t(9;11)(p21-22;q23) [MLL/AF9], t(10;11)(p11-13;q23) [MLL/AF10], t(11;19)(q23;p13.1) [MLL/ELL], and t(11;19)(q23; p13.3) [MLL/ENL] in cell lines, as well as in patient material.
Leukemia 2001 Aug
PMID:Paired multiplex reverse-transcriptase polymerase chain reaction (PMRT-PCR) analysis as a rapid and accurate diagnostic tool for the detection of MLL fusion genes in hematologic malignancies. 1214 6

We established a real-time PCR method that can simultaneously detect 10 different fusion transcripts (major, minor and micro BCR/ABL, AML1/MTG8, PML/RARalpha, CBFbeta/MYH11, TEL/AML1, E2A/PBX1, MLL/AF4, and MLL/AF9) together with Wilms' tumor gene (WT1) transcripts. This screening method allowed the processing of six specimens concomitantly and required only one working day from RNA extraction to final results. Fifty-seven bone marrow (BM) samples from patients with acute leukemia were retrospectively screened for the presence of fusion and WT1 transcripts without knowledge of the cytogenetic data, and the fusion transcripts were detected in 20 of 57 samples (35.1%). The concordance between the present method and cytogenetic analysis was examined in 38 samples in which the cytogenetic data were available. In 12 of 38 samples, the PCR results agreed with the cytogenetic data, whereas in 4 of the remaining 26 samples, the translocations were detected by real-time PCR alone because of the insufficient number of metaphases obtained and presumably the submicroscopic or masked translocations. The WT1 levels ranged from 400 to 690,000 copies/microg RNA in BM from leukemia patients, whereas 0-470 copies/microg RNA were found in BM cells from BMT donors. This real-time PCR method enables rapid and efficient characterization of acute leukemia in addition to subsequent evaluation of minimal residual diseases.
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PMID:Rapid screening of leukemia fusion transcripts in acute leukemia by real-time PCR. 1261 15

Precursor B-acute lymphoblastic leukemia (pB-ALL) is a heterogeneous disease and multiparameter flow cytometry, molecular genetics, and cytogenetic studies have all contributed to classification of subgroups with prognostic significance. Recently, gene expression microarray technology has been used to investigate lymphoblastic leukemias, demonstrating that known and novel pB-ALL subclasses can be separated on the basis of gene expression profiles. The strength of microarray technique lays in part in the multivariate nature of the expression data. We propose a parallel multiparametric approach based on immunophenotypic flow-cytometry expression data for the analysis of leukemia patients. Specifically, we tested the potential of this approach on a data set of 145 samples of pediatric pB-ALL that included 46 samples positive for mixed lineage leukemia (MLL) translocations (MLL+) and 99 control pB-ALLs, negative for this translocation (MLL-). The expression levels of 16 marker proteins have been monitored by four-color flow cytometry using a standardized diagnostic panel of antibodies. The protein expression database has been then analyzed using those univariate and multivariate computational techniques normally applied to mine and model large microarray data sets. Marker protein expression profiling not only allowed separating pB-ALL cases with an MLL rearrangement from other ALLs, but also demonstrates that MLL+ leukemias constitute a heterogeneous group in which MLL/AF4 leukemias represent a homogenous subclass described by a specific expression fingerprint.
Leukemia 2003 Aug
PMID:Computational analysis of flow-cytometry antigen expression profiles in childhood acute lymphoblastic leukemia: an MLL/AF4 identification. 1288 43

Infant acute lymphoblastic leukemia (ALL) is frequently characterized by the t(4;11)(q21;q23) cytogenetic abnormality encoding the MLL/AF4 oncogene, increased HOX gene expression and a pro-B/monocytoid phenotype. We have previously established a novel MLL/AF4-positive cell line, B-lineage 3 (BLIN-3), which retains several features of normal B-lineage development (functional Ig gene rearrangement and apoptotic sensitivity to stromal cell withdrawal) not generally observed in infant ALL. We now use microarray analysis to identify patterns of gene expression in BLIN-3 that may modulate MLL/AF4 oncogenesis and contribute to the retention of normal B-lineage developmental characteristics. Comparison of 6815 expressed genes in BLIN-3 with published microarray data on leukemic blasts from t(4;11) patients indicated that BLIN-3 was unique in lacking the expression of certain HOX-A cluster genes. These results were validated by RT-PCR showing no expression of HOX A7 or HOX A9 in BLIN-3. A HOX C8 promoter reporter was active in BLIN-3, indicating that lack of HOX gene expression in BLIN-3 was not due to a nonfunctional MLL/AF4. Our results suggest that B-lineage development can proceed in t(4;11) leukemic blasts in the absence of HOX-A gene expression.
Leukemia 2003 Dec
PMID:B-cell development in the presence of the MLL/AF4 oncoprotein proceeds in the absence of HOX A7 and HOX A9 expression. 1456 13

Improved leukemia classification and tailoring of therapy have greatly improved patient outcome particularly for children with acute leukemia (AL). Using immunophenotyping, molecular genetics and cytogenetics the low hanging fruits of biomedical research have been successfully incorporated in routine diagnosis of leukemia subclasses. Future improvements in the classification and understanding of leukemia biology will very likely be more slow and laborious. Recently, gene expression profiling has provided a framework for the global molecular analysis of hematological cancers, and high throughput proteomic analysis of leukemia samples is on the way. Here we consider classification of acute leukemia samples by flow cytometry using the marker proteins of immunophenotyping as a component of the proteome. Marker protein expressions are converted into quantitative expression values and subjected to computational analysis. Quantitative multivariate analysis from panels of marker proteins has demonstrated that marker protein expression profiles can distinguish MLLre from non-MLLre ALL cases and also allow to specifically distinguish MLL/AF4 cases. Potentially, these quantitative expression analyses can be used in clinical diagnosis. Immunophenotypic data collection using flow cytometry is a fast and relatively easily accessible technology that has already been implemented in most centers for leukemia diagnosis and the translation into quantitative expression data sets is a matter of flow cytometer settings and output calibration. However, before application in clinical diagnostics can occur it is crucial that quantitative immunophenotypic data set analysis is validated in independent experiments and in large data sets.
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PMID:Acute leukemia subclassification: a marker protein expression perspective. 1520 97

Identification of chromosome rearrangements is of importance for exact diagnosis, risk assessment, and therapy in blood malignancies. A new method was proposed for rapid and accurate identification of leukemia forms caused by chromosome rearrangements involving MLL (11q23). The method combines reverse transcription-multiplex PCR and hybridization with an oligonucleotide microarray. The microarray was designed to detect the five most common MLL rearrangements: t(4;11) MLL/AF4, t(9;11) MLL/AF9, t(11;19) MLL/ELL, t(11;19) MLL/ENL, and dup(11) MLL/MLL. With clinical specimens, the method was shown to efficiently identify the chromosome translocations in leukemia patients.
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PMID:[Analysis of chromosome translocations involving MML by hybridization with an oligonucleotide microarray]. 1528 14

Open questions in the pathogenesis of childhood acute lymphoblastic leukemia (ALL) are which hematopoietic cell is target of the malignant transformation and whether primitive stem cells contribute to the leukemic clone. Although good-prognosis ALL is thought to originate in a lymphoid progenitor, it is unclear if this applies to high-risk ALL. Therefore, immature CD34(+)CD19(-) bone marrow cells from 8 children with ALL/t(9;22) and 12 with ALL/t(4;11) were purified and analyzed by fluorescence in situ hybridization, reverse transcription-PCR (RT-PCR), and colony assays. Fifty-six percent (n = 8, SD 31%) and 68% (n = 12, SD 26%) of CD34(+)CD19(-) cells in ALL/t(9;22) and ALL/t(4;11), respectively, carried the translocation. In addition, 5 of 168 (3%) and 22 of 228 (10%) myeloerythroid colonies expressed BCR/ABL and MLL/AF4. RT-PCR results were confirmed by sequence analysis. Interestingly, in some patients with ALL/t(4;11), alternative splicing was seen in myeloid progenitors compared with the bulk leukemic population, suggesting that these myeloid colonies might be part of the leukemic cell clone. Fluorescence in situ hybridization analysis, however, shows that none of these myeloid colonies (0 of 41 RT-PCR-positive colonies) originated from a progenitor cell that carries the leukemia-specific translocation. Thus, leukemic, translocation-positive CD34(+)CD19(-) progenitor/stem cells that were copurified by cell sorting were able to survive in these colony assays for up to 28 days allowing amplification of the respective fusion transcripts by sensitive RT-PCR. In conclusion, we show that childhood high-risk ALL/t(9;22) and t(4;11) originate in a primitive CD34(+)CD19(-) progenitor/stem cell without a myeloerythroid developmental potential.
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PMID:Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells. 1573 32


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