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Query: UMLS:C0596978 (Leukemia)
 15,069 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Modern therapy for pediatric acute lymphoblastic leukemia (ALL) is based on the principle of risk stratification. One of the most important laboratory features used to accurately risk stratify patients is the presence of specific chromosomal translocation within the leukemic blasts. In this paper, we describe a multiplex reverse transcriptase-polymerase chain reaction (RT-PCR) assay for the accurate, sensitive, and rapid identification of chimeric transcripts encoded by the major risk-stratifying translocations of pediatric ALL. This assay will identify both the CML- and ALL-type BCR-ABL transcripts encoded by the t(9;22), all described variants of the E2A-PBX1 transcripts encoded by the t(1;19), the MLL-AF4 transcripts encoded by the t(4;11), and all variants of TEL-AML1 encoded by the t(12;21). In addition, we have developed a reverse dot-blot detection system as an alternative to traditional post-PCR Southern blot analysis. Application of this combined assay to the analysis of 70 leukemic samples and five cell lines resulted in a complete concordance between this multiplex assay and individual PCR reactions. The characteristics of the multiplex assay suggest that its application to routine clinical screening will significantly improve the ability of clinical laboratories to accurate risk stratify pediatric ALL patients.
Leukemia 1998 Dec
PMID:A multiplex RT-PCR assay for the detection of chimeric transcripts encoded by the risk-stratifying translocations of pediatric acute lymphoblastic leukemia. 984 30

Leukemia in the first year of life is extremely rare world-wide. However, unlike leukemias in older children, nearly 75% of infant leukemias demonstrate a specific abnormality involving a gene, MLL, on chromosome band 11q23. Molecular studies suggest strongly that these leukemias occur in utero. Treatment-related acute myeloid leukemias (AML), associated with specific chemotherapeutic agents that inhibit DNA topoisomerase II (topo 2), also manifest identical abnormalities involving the MLL gene. This led us to speculate that maternal exposure during pregnancy to environmental agents that inhibit DNA topo 2 may be associated with the development of leukemia in infants. DNA topo 2 inhibitors have been found in specific fruits and vegetables, and in soy, coffee, wine, tea and cocoa, as well as in certain pesticides, solvents and medications. In a preliminary study, we reinterviewed mothers of infant cases and their matched controls who had participated previously in 1 of 3 epidemiologic studies of childhood leukemia conducted by the Children's Cancer Group over a 10-year period. We evaluated potential DNA topo 2 inhibitor exposure through maternal diet and medications. Of the 84 original matched sets who were reinterviewed, there was no positive association with increasing maternal consumption of DNA topo 2 inhibitor-containing foods either for the overall group or for infants in the acute lymphoblastic leukemia stratum. However, there was an approximately 10-fold higher risk of infant AML with increasing maternal consumption of DNA topo 2 inhibitor-containing foods. The assay to screen environmental agents that inhibit DNA topo 2 has been established and new inhibitors are being identified routinely.
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PMID:Maternal diet and infant leukemia: a role for DNA topoisomerase II inhibitors? 987 73

Myeloperoxidase (MPO) is found in the azurophilic granules of normal myelocytic cells. Cytochemical staining for MPO activity is used clinically to distinguish myeloid from acute lymphoid leukemias (ALL). However, using a highly sensitive RT-PCR technique, it is possible to detect MPO mRNA in otherwise clear ALL. The significance of this finding remains poorly understood. We have extended our observations to a series of 57 patients with the primary diagnosis of ALL (46 patients tested at diagnosis and 11 cases at relapse). We identified 25 cases (43.8%) of MPO mRNA(+)/enzyme(-) ALL (17 B cell and eight T cell lineage). Expression of myeloid antigens (CD13 or CD33) were detected in nine of them, and remarkably, 18 cases (72%) displayed CD34. Of these 25 MPO mRNA(+) leukemias, 10 (40%) are Bcr-Abl positive (with P210 fusion transcript in five patients while the five remaining cases carried P190 transcript). Moreover, 11 of 16 myeloid negative cases were also negative for any type of Bcr-Abl and MLL rearrangement, indicating that MPO mRNA positivity is not either invariably related to that chromosomal abnormality or necessarily associated with the presence of other myeloid differentiation features. Interestingly, six of these 11 cases are T-ALL, suggesting the presence of some overlapping phase for T and myeloid lineage commitment. Taken together, these findings could suggest a separate biological disease with immature origin and bipotential differentiation capability, which involves B and T-ALL subtypes and should lead to new investigations regarding their prognostic impact.
Leukemia 1999 Feb
PMID:Genetic, phenotypic and clinical features of acute lymphoblastic leukemias expressing myeloperoxidase mRNA detected by RT-PCR. 1158 32

The MLL gene, located on chromosome band 11q23 is fused to different partner genes as a result of various chromosomal translocations in hematopoietic malignancies. A t(1;11) (q21;q23) resulting in a MLL-AF1q fusion gene has previously been reported. Cytogenetic studies on six cases are reported, including one three-way translocation. FISH analysis using a YAC encompassing the MLL gene and a YAC encompassing the AF1q locus showed splitting in three cases and two patients, respectively. PCR analysis of two cases confirmed that AF1q is specifically associated with t(1;11)(q21;q23). The MLL-AF1q fusion mRNA was similar to that previously described in one case and involved MLL exon 7 in the other. This study confirms the specific involvement of AF1q in t(1;11) (q21;q23)-positive acute leukemia with monocytic involvement.
Leukemia 1999 Feb
PMID:MLL-AF1q fusion resulting from t(1;11) in acute leukemia. 1002 7

Recent molecular-genetic studies have revealed that in the majority of patients with secondary leukemia induced by topoisomerase II (topo II) inhibitors and also with infantile acute leukemia (IAL), the breakpoints are clustered within scaffold attachment regions (SARs) of 3'-MLL-bcr near exon 9. Genistein, abundant in soybeans, is reported to be a potent nonintercalative topo II inhibitor. It interferes with the break-reseal reaction of topo II by stabilizing a cleavable complex, which in the presence of detergents, results in DNA strand breaks. The present study revealed that genistein induced chromatid-type aberrations, in which chromatid exchanges are often observed. Genistein seems to act in a manner very similar to that of VP-16, although the latter is reported to produce both chromatid- and chromosome-type aberrations. In view of this pharmacological similarity between genistein and VP-16, and also the similarity of breakpoint clustering regions within the MLL gene in reported cases with secondary leukemia and IAL, genistein may be largely responsible for the development of IAL.
Leukemia 1999 Mar
PMID:Infantile leukemia and soybeans--a hypothesis. 1072 Jan 57

MLL (ALL1, Htrx, HRX), which is located on chromosome band 11q23, frequently is rearranged in patients with therapy-related acute myeloid leukemia who previously were treated with DNA topoisomerase II inhibitors. In this study, we have identified a fusion partner of MLL in a 10-year-old female who developed therapy-related acute myeloid leukemia 17 months after treatment for Hodgkin's disease. Leukemia cells of this patient had a t(11;17)(q23;q25), which involved MLL as demonstrated by Southern blot analysis. The partner gene was cloned from cDNA of the leukemia cells by use of a combination of adapter reverse transcriptase-PCR, rapid amplification of 5' cDNA ends, and BLAST database analysis to identify expressed sequence tags. The full-length cDNA of 2.8 kb was found to be an additional member of the septin family, therefore it was named MSF (MLL septin-like fusion). Members of the septin family conserve the GTP binding domain, localize in the cytoplasm, and interact with cytoskeletal filaments. A major 4-kb transcript of MSF was expressed ubiquitously; a 1.7-kb transcript was found in most tissues. An additional 3-kb transcript was found only in hematopoietic tissues. By amplification with MLL exon 5 forward primer and reverse primers in MSF, the appropriately sized products were obtained. MSF is highly homologous to hCDCrel-1, which is a partner gene of MLL in leukemias with a t(11;22)(q23;q11.2). Further analysis of MSF may help to delineate the function of MLL partner genes in leukemia, particularly in therapy-related leukemia.
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PMID:MSF (MLL septin-like fusion), a fusion partner gene of MLL, in a therapy-related acute myeloid leukemia with a t(11;17)(q23;q25). 1033 4

Infants less than 1 year of age at diagnosis of acute lymphoblastic leukemia (ALL) have a poor prognosis, which has been attributed primarily to a breakpoint in chromosomal band 11q23 or the MLL gene. Most infants with an 11q23 breakpoint have a t(4;11)(q21 ;q23). We studied the cytogenetics of the leukemia cells of 56 infants on CCG-1883, a single-arm clinical treatment protocol for infant ALL. Twenty-one patients had t(4;11)(q21;q23), seven had other rearrangements with breakpoints in 11q23 (other 11q23), 16 had normal chromosomes, two had t(1;19)(q32;p13), one had >50 chromosomes, and nine had non-recurring structural abnormalities. To determine whether there is a difference in outcome for infants with t(4;11), other 11q23 and the remaining patients, we compared event-free survival (EFS) and other clinical and laboratory features of the above infants. Infants without t(4;11) and those with other 11q23 rearrangements had significantly better EFS than those with t(4;11) (P= 0.007 and P= 0.02, respectively). t(4;11) correlated with age less than 6 months and with CD10 negativity, both of which also were poor prognostic indicators. After adjustment for age, there was still a significant difference in EFS between patients with t(4;11) and those with other 1lq23 rearrangements (P=0.02), and between patients with t(4;11) and those without t(4;11) (P=0.04). Among CD10 negative patients, t(4;11) was associated with a worse EFS (P=0.01). Multivariate analysis showed that after adjusting for a variety of clinical and laboratory features, t(4;11) was the most important prognostic factor for poor outcome, and patients with other 11q23 rearrangements had as good an outcome as the remaining patients without t(4;11).
Leukemia 1999 May
PMID:Cytogenetic studies of infant acute lymphoblastic leukemia: poor prognosis of infants with t(4;11) - a report of the Children's Cancer Group. 1037 70

To explore the possibility that deregulated HOX gene expression might commonly occur during leukemic hematopoiesis, we compared the relative levels of expression of these and related genes in phenotypically and functionally defined subpopulations of AML blasts and normal hematopoietic cells. Initially, a semi-quantitative RT-PCR technique was used to amplify total cDNA from total leukemic blast cell populations from 20 AML patients and light density cells from four normal bone marrows. Expression of HOX genes (A9, A10, B3 and B4), MEIS1 and MLL was easily detected in the majority of AML samples with the exception of two samples from patients with AML subtype M3 (which expressed only MLL). Low levels of HOXA9 and A10 but not B3 or B4 were seen in normal marrow while MLL was easily detected. PBX1a was difficult to detect in any AML sample but was seen in three of four normal marrows. Cells from nine AML patients and five normal bone marrows were FACS-sorted into CD34+CD38-, CD34+CD38+ and CD34-subpopulations, analyzed for their functional properties in long-term culture (LTC) and colony assays, and for gene expression using RT-PCR. 93 +/- 14% of AML LTC-initiating cells, 92 +/- 14% AML colony-forming cells, and >99% of normal LTC-IC and CFC were CD34+. The relative level of expression of the four HOX genes in amplified cDNA from CD34- as compared to CD34+CD38- normal cells was reduced >10-fold. However, in AML samples this down-regulation in HOX expression in CD34- as compared to CD34+CD38- cells was not seen (P < 0.05 for comparison between AML and normal). A similar difference between normal and AML subpopulations was seen when the relative levels of expression of MEIS1, and to a lesser extent MLL, were compared in CD34+ and CD34- cells (P < 0.05). In contrast, while some evidence of down-regulation of PBX1a was found in comparing CD34- to CD34+ normal cells it was difficult to detect expression of this gene in any subpopulation from most AML samples. Thus, the down-regulation of HOX, MEIS1 and to some extent MLL which occurs with normal hematopoietic differentiation is not seen in AML cells with similar functional and phenotypic properties.
Leukemia 1999 May
PMID:Expression of HOX genes, HOX cofactors, and MLL in phenotypically and functionally defined subpopulations of leukemic and normal human hematopoietic cells. 1037 71

A diagnosis of pro-B acute lymphoblastic leukemia (ALL) with CD15+ was made in a 42-year-old woman, 12 months after the treatment of uterine adenocarcinoma by carboplatinum, anthracyclines, etoposide and radiotherapy. Molecular cytogenetic studies revealed a karyotype with multiple chromosome changes, including the t(4;11)(q21;q23) and a 17p-chromosome, with MLL disruption and 17p13/p53 gene deletion in 86% of the cells. A p53 exon 6 mutation was documented, resulting in p53 protein stabilization, with 20% of the cells reacting with the 1801 anti-p53 monoclonal antibody. Dual-color FISH using MLL and p53 probes was performed on peripheral blood smears, providing direct evidence of the involvement of the blast cells and of the granulocytic lineage. Only a partial, shortlasting response was obtained by induction treatment, confirming that a poor prognosis is associated with therapy-related ALL with the 4;11 translocation.
Leukemia 1999 May
PMID:Therapy-related adult acute lymphoblastic leukemia with t(4;11)(q21; q23): MLL rearrangement, p53 mutation and multilineage involvement. 1037 73

Of 29 infants with acute myeloid leukemia (AML), 14 (48%) had various 11q23 translocations. MLL rearrangements were examined in 21 of the 29 patients, and 11 (52%) showed the rearrangements. 11q23 translocations and/or MLL rearrangements were found in 17 (58%) of the 29 patients. While all but one of the 17 patients with 11q23/MLL rearrangements had M4 or M5 type of the FAB classification, the 12 patients without such rearrangements had various FAB types, including M2, M4, M4EO, M6 and M7. Of the 12 patients with other chromosome abnormalities or normal karyotypes, two had inv(16) ort(16;16), one had t(1;22)(p13;q13), and two had a novel translocation, t(7;12)(q32;p13). The breakpoint on 12p of the t(7;12) was assigned to intron 1 or the region just upstream of exon 1 of the TEL/ETV6 gene by fluorescence in situ hybridization. The event-free survival at 5 years for the 17 patients with 11q23/MLL rearrangements was 42.2%, and that for the 12 patients without such rearrangements was 31.3% (P = 0.5544). 11q231MLL rearrangements have been frequently reported and a poor prognosis in infant acute lymphoblastic leukemia implied. Our study showed that while 11q23/MLL rearrangements were also common in infant AML, AML infants with such rearrangements had a clinical outcome similar to that of AML infants without such rearrangements.
Leukemia 1999 Jul
PMID:Chromosome abnormalities and MLL rearrangements in acute myeloid leukemia of infants. 1040 Apr 16


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