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

We describe two new human leukemia cell lines, MOLM-13 and MOLM-14, established from the peripheral blood of a patient at relapse of acute monocytic leukemia, FAB M5a, which had evolved from myelodysplastic syndrome (MDS). Both cell lines express monocyte-specific esterase (MSE) and MLL-AF9 fusion mRNA. Gene fusion is associated with a minute chromosomal insertion, ins(11;9)(q23;p22p23). MOLM-13 and MOLM-14 are the first cell lines with, and represent the third reported case of, MLL gene rearrangement arising via chromosomal insertion. Both cell lines carry trisomy 8 which was also present during the MDS phase, as well as the most frequent trisomies associated with t(9;11), ie, +6, +13, +19 variously present in different subclones. Despite having these features in common, differences in antigen expression were noted between the two cell lines: that of MOLM-13 being CD34+, CD13-, CD14-, CD15+, CD33+; whereas MOLM-14 was CD4+, CD13+, CD14+, CD15+, CD33+. Differentiation to macrophage-like morphology could be induced in both cell lines after stimulation with INF-gamma alone, or in combination with TNF-alpha, which treatment also induced or upregulated, expression of certain myelomonocyte-associated antigens, including CD13, CD14, CD15, CD64, CD65 and CD87. Together, these data confirm that both cell lines are likely to be novel in vitro models for studying monocytic differentiation and leukemogenesis.
Leukemia 1997 Sep
PMID:Two acute monocytic leukemia (AML-M5a) cell lines (MOLM-13 and MOLM-14) with interclonal phenotypic heterogeneity showing MLL-AF9 fusion resulting from an occult chromosome insertion, ins(11;9)(q23;p22p23). 930

A novel variant of the chimerical MLL-AF10 mRNA transcript was detected in a pediatric patient with acute myeloid leukemia (AML) by a new asymmetric reverse-transcription polymerase chain reaction (ART-PCR) method. Sequence analysis of the fusion region on the amplified cDNA fragment showed an in-frame joining of exon e5 of the MLL gene and position 1931 of the cDNA sequence of the AF10 gene, giving rise to a new MLL-AF10 transcript. The presence of the new chimerical mRNA product in a sample from the patient was confirmed by classical RT-PCR.
Leukemia 1997 Sep
PMID:A novel MLL-AF10 fusion mRNA variant in a patient with acute myeloid leukemia detected by a new asymmetric reverse transcription PCR method. 930 18

The MLL gene at chromosome 11, band q23, is involved in translocations with as many as 40 different chromosomal bands. Virtually all breakpoints occur within an 8.3 kb BamHI fragment and result in 5' MLL fused to partner genes in a 5'-3' orientation. The translocation t(9;11)(p22;q23), which results in the fusion of MLL to AF9, is the most common of the 11q23 chromosomal abnormalities observed in de novo acute myeloid leukemia (AML), in therapy related leukemia (t-AML), and rarely in acute lymphoblastic leukemia (ALL). We have studied 24 patients with a t(9;11) and an MLL rearrangement, including 19 patients with AML, four with t-AML, and one with ALL. To understand the mechanisms of this illegitimate recombination, we cloned and sequenced the t(9;11) translocation breakpoint junctions on both derivative chromosomes from one AML patient and from the Mono Mac 6 (MM6) cell line, which was derived from a patient with AML. Two different complex junctions were noted. In the AML patient, both chromosome 11 and 9 breaks were staggered, occurred in Alu DNA sequences, and resulted in a 331 bp duplication. In the MM6 cell line, breaks in chromosomes 11 and 9 were also staggered, but, in contrast to the finding in the AML patient, the breaks did not involve Alu DNA sequences and resulted in a 664 bp deletion at the breakpoints. Using reverse transcriptase (RT-) PCR, we analyzed 11 patient samples, including the two just described, for MML-AF9 fusions. The fusion occurred in six of seven AML patients, two of two t-AML patients, one patient with ALL, and in the MM6 cell line. Interestingly, all of the breaks within the AF9 gene in AML patients occurred in the central AF9 exon, called Site A by others, whereas in the single ALL patient the breakpoint mapped to a more 3' region of the AF9 gene. Our data, when combined with those of others, suggest that the fusion point within the AF9 gene, and thus the amount of AF9 material included in the MLL-AF9 fusion gene product, may influence the phenotype of the resulting leukemia. This further supports the proposal that the MML translocation partner genes play a critical role in the leukemogenic process.
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PMID:Identification of complex genomic breakpoint junctions in the t(9;11) MLL-AF9 fusion gene in acute leukemia. 933 69

Advances in the molecular characterization of leukemic cells have greatly improved the precision of diagnosis and treatment assignment as well as the monitoring of residual disease in both acute lymphoblastic leukemia and acute myeloid leukemia. Currently, specific genetic rearrangements can be identified in as many as 50% of children with either acute lymphoblastic leukemia or acute myeloid leukemia. The genes p16 (or MTS1) and TEL/AML1 are now respectively recognized as the most common tumor suppressor and fusion genes in childhood acute lymphoblastic leukemia. Increasingly, contemporary protocols for the acute leukemias are relying on genetic information to guide treatment decisions. Examples include the use of allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia with the BCR-ABL fusion gene or MLL rearrangement, and for acute myeloid leukemia with monosomy 7; antimetabolite-based therapy for acute lymphoblastic leukemia cases with hyperdiploidy of more than 50 chromosomes (DNA index > or = 1.16); and retinoic acid and anthracycline-containing regimens for the acute promyelocytic acute myeloid leukemia subtype with PML-RARA fusion. Other efforts are being made to reduce the long-term sequelae of treatment. Indeed, extended intrathecal therapy and intensive systemic chemotherapy will, in all likelihood, replace cranial irradiation as subclinical central nervous system therapy for patients with intermediate-risk acute lymphoblastic leukemia, and perhaps even for those with high-risk acute lymphoblastic leukemia. The challenge now is to identify specific treatments for other genetically defined subtypes of leukemia. This goal will be realized only through protocol-based studies employing uniform criteria for defining risk status.
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PMID:Acute leukemia in children. 937 85

Unlike childhood leukemia diagnosed at later ages, where there is an excess risk in males, there is a notable female predominance in infant leukemia. Since abnormalities involving the MLL gene are frequent in infants with leukemia, we asked whether there are gender differences with respect to MLL gene status. Data were combined from seven published molecular studies that examined MLL abnormalities in infants with leukemia. Of 239 cases with conclusive information, there was a female predominance in cases with an MLL abnormality (female:male ratio 1.3); this was in marked contrast to cases with normal germline MLL (female:male ratio, 0.7). These potential gender-dependent MLL frequencies should be explored in large populations of infant leukemia and, if confirmed, future investigations could be directed toward potential etiologic mechanisms.
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PMID:MLL rearrangements in infant leukemia: is there a higher frequency in females? 937 88

We used a new approach called panhandle polymerase chain reaction (PCR) to clone an MLL genomic translocation breakpoint in a case of acute lymphoblastic leukemia of infancy in which karyotype analysis was technically unsuccessful and did not show the translocation partner. Panhandle PCR amplified known MLL sequence 5' of the breakpoint and 3' sequence from the unknown partner gene from a DNA template with an intrastrand loop schematically shaped like a pan with a handle. The 7-kb panhandle PCR product contained the translocation breakpoint in MLL intron 8. The partner DNA included unique nonrepetitive sequences, Alu and mammalian apparent LTR-retrotransposon (MaLR) repetitive sequences, and a region of homology to expressed sequence tags. MaLR sequences have not been found before near leukemia-associated translocation breakpoints. The nonrepetitive sequences were not homologous to known partner genes of MLL. Screening of somatic cell hybrid and radiation hybrid lines by PCR and fluorescence in situ hybridization analysis of normal metaphase chromosomes mapped the partner DNA to chromosome band 4q21. Reverse transcriptase-PCR identified an MLL-AF-4 chimeric mRNA, indicating that panhandle PCR identified a fusion of MLL with a previously uncharacterized AF-4 intronic sequence. Panhandle PCR facilitates cloning translocation breakpoints and identifying unknown partner genes.
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PMID:Panhandle polymerase chain reaction amplifies MLL genomic translocation breakpoint involving unknown partner gene. 938 82

Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.
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PMID:Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. 939 Nov 33

Although the presence of a chromosome 11q23 breakpoint is of recognized poor prognosis in acute lymphoblastic leukemia, its prognostic significance in acute myeloid leukemia (AML) has been the object of conflicting reports, perhaps reflecting the possibility of different entities. It has been found that only typical and generally balanced 11q23 chromosomal anomalies involve the MLL gene while atypical and generally unbalanced do not. To determine whether these two categories of AML patients had different initial characteristics and evolution, supporting different pathogenetic mechanisms, we analyzed clinical and biologic characteristics of newly diagnosed AML patients with balanced 11q23 breakpoint and/or MLL rearrangement seen over a 10-year period in our institution and compared them to cases with unbalanced 11q23 anomaly seen over the same period. These two categories of patients were compared with newly diagnosed patients with normal karyotype and no MLL rearrangement when tested, seen over the same period of time and treated similarly. Over this period, 442 newly diagnosed adult (> 15 years) AML seen in our institution had a successful karyotype performed before any therapy. Thirty-six cases (8%) had a chromosome 11q23 breakpoint including 19 cases with a balanced translocation or inversion and 17 cases with an unbalanced anomaly. Eighty-seven recently diagnosed cases of AML, for whom frozen cellular material was available, were analyzed by Southern blot for the presence of MLL gene rearrangement. Fourteen cases (16% of the tested cases) had a rearrangement of the MLL gene, including seven cases with an apparently successful karyotype not showing any 11q23 breakpoint and two cases with no available karyotype. The only case with unbalanced 11q23 chromosomal anomaly which was tested had no MLL rearrangement. There was a clear-cut clinical difference between the 28 patients having a balanced 11q23 anomaly/MLL rearrangement and the 17 patients having an unbalanced chromosomal anomaly: AML with unbalanced 11q23 anomalies occurred in older patients (P = 0.07) tended to be less frequently associated with previous exposure to topoisomerase II-active drugs and with M4/M5 FAB cytological subtypes, were always associated with other chromosomal anomalies (P < 0.0001), expressed more frequently the CD34 antigen (P = 0.05) and were of considerably poorer prognosis for achievement of CR (P = 0.005) and survival (P = 0.0005). When compared to the control population, patients with balanced anomalies had more frequent history of toxic exposure (P = 0.0003) particularly to topoisomerase II-active drugs, tended to be more frequently of M4/M5 FAB subtypes (P = 0.07), expressed more frequently HLA-DR antigen (P = 0.02) and had shorter DFS (P = 0.02). Patients with unbalanced anomalies had more frequent splenomegaly (P = 0.009), lower WBC count (P = 0.04), and much poorer prognosis for CR achievement (P = 0.0001), survival (P < 0.0001) and DFS (P = 0.01). This study confirms the high frequency of 11q23 chromosomal breakpoint/MLL rearrangement in adult AML and the probable existence of two different entities with different clinical features according to the presence of a balanced or unbalanced cytogenetic abnormality, the latter being not associated with MLL rearrangement.
Leukemia 1998 Jan
PMID:Clinical and biological characteristics of adult de novo and secondary acute myeloid leukemia with balanced 11q23 chromosomal anomaly or MLL gene rearrangement compared to cases with unbalanced 11q23 anomaly: confirmation of the existence of different entities with 11q23 breakpoint. 943 17

p16 and p15 genes are putative tumor suppressor genes located on chromosome 9p21. In acute leukemias, alterations of p16 and p15 genes have been reported to occur exclusively in lymphoid lineage. We analyzed alterations of p16 and p15 genes in 46 acute leukemias with MLL gene rearrangements by Southern blot analysis, and investigated the association with clinical characteristics. We identified homozygous deletion of p16 and p15 genes in five (19%) of 27 acute lymphoblastic leukemias (ALLs) and in two (11%) of 19 acute myeloid leukemias (AMLs). Patients with homozygous deletion of p16 and p15 genes showed higher average leukocyte counts (343 x 10(9)/l vs 271 x 10(9)/l) and lower estimated 2-year survival rates than those with normal p16 and p15 genes (14.3 vs 30.7%), although the differences were not statistically significant. In addition, we investigated mutation of p16 gene by polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) in 31 patients, but no mutation was found in the patients tested. Our results suggest that alterations of p16 and p15 genes are involved in a subset of acute leukemias with MLL gene rearrangement not only of lymphoid but also of myeloid phenotype. Homozygous deletion of p16 and p15 genes may be a possible adverse prognostic factor, although further analysis would be needed to confirm it.
Leukemia 1997 Dec
PMID:Alterations of p16 and p15 genes in acute leukemia with MLL gene rearrangements and their correlation with clinical features. 944 29

Therapy-related leukemia and myelodysplastic syndrome (TRL/MDS) in Japan were analysed in a multi-institution study to assess clinical, cytogenetic aspects, and prognostic factor. From 1985 to 1994, 405 cases of adult TRL/MDS were diagnosed and overall percentage of TRL/MDS in leukemia and MDS was 1.9%. Median age was 61 years old. The median latency from primary malignancies was 53.4 months, which latency was significantly shorter in the patients treated with chemotherapy. Primary malignancies were hematologic in 39%. Common symptoms were fatigue/ weakness and anemia. Chromosome 7,5, and 11 were frequently involved. MLL gene rearrangement were detected in 12 of 64 analysed cases. Overall median survival was 10.0 months. Body weight loss, neurologic abnormality, hypoproteinemia, hypofibrinogenemia, proteinuria, lack of Auer rods, and 5q-were prognostic factors in TRL/MDS. This large population study documented some datas useful for the prevention of TRL/MDS.
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PMID:[Therapy-related leukemia and myelodysplastic syndrome: a multi-institution study in Japan]. 946 95


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