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J D Rowley

Publications and source records attributed to J D Rowley.

At least 109 records · Page 6Linked to original sources
PubMed1994

Clonal, nonconstitutional rearrangements of the MLL gene in infant twins with acute lymphoblastic leukemia: in utero chromosome rearrangement of 11q23.

Rearrangements of chromosome band 11q23 are common in infant leukemias, comprising more than 70% of the observed chromosome abnormalities in children less than 1 year of age. The MLL gene, which is located at the 11q23 breakpoint in infant, childhood, and adult acute leukemias, has been cloned and has homology to the Drosophila trithorax gene. The breakpoints in MLL are restricted to an 8.3-kilobase pair (kb) region of the gene that is involved in translocations with as many as 29 other chromosomal regions in a number of phenotypically distinct acute leukemias. We have detected an identical, clonal, nonconstitutional rearrangement of the MLL gene in peripheral blood cells from a pair of female infants twins with acute lymphoblastic leukemia (ALL) and a t(11;19)(q23;p13.3). The detection of nonidentical IGH rearrangements suggests that the MLL rearrangement took place in a B-cell precursor or hematopoietic stem cell in one twin which was transferred in utero to the other fetus resulting in ALL with an identical aneuploid karyotype in both infants. We speculate that the other MLL-related infant leukemias may also develop in utero, and that the rearrangements may occur consistently in stem cells or early precursor cells, accounting for the frequency of mixed-lineage leukemia in infants.

Chromosomes, Human, Pair 11↗
PubMed1994

DNA rearrangements and altered transcripts of the MLL gene in a human T-ALL cell line Karpas 45 with a t(X;11) (q13;q23) translocation.

Translocations involving chromosome band 11q23 are found in both lymphoid and myeloid leukemias as well as in lymphomas, in these translocations. The chromosomes most frequently involved in reciprocal translocations include chromosomes 4, 6, 9, and 19, and we and others have reported that chromosomes 1, 2, 10, 15, 17, 18, 22, and X are also involved. In the cell line Karpas 45, which has a t(X;11) (q13;q23) translocation, we report here that the MLL gene is rearranged and that there are two altered transcripts of MLL that come from the der(11) chromosome.

Chromosomes, Human, Pair 11↗
PubMed1994

Analysis of tumor suppressor gene on human chromosome 9 in mouse x human somatic cell hybrids.

Deletions of the short arm of human chromosome 9 (9p) are common in human leukemia and solid tumors. The minimum region of overlap of these deletions, located between the interferon genes and the methylthioadenosine phosphorylase gene, is partially syntenic with a region of mouse chromosome 4 that has tumor suppressor activity. Somatic cell hybrids between tumorigenic, MTAP-deficient, mouse L cells, and MTAP-competent human cells containing either a normal copy of 9p or a 9p with a deletion involving band 9p21 were selected in culture conditions that require MTAP activity for continued growth. Somatic cell hybrids that contained a normal copy of 9p rarely formed tumors in nude mice. Cells from the rare tumors that grew had lost the normal 9p. Hybrid cells that contained a 9p with deletions formed tumors more frequently, and cells from these tumors retained the 9p deletion chromosome. These results provide evidence that a tumor suppressor gene (or genes) is located on human chromosome 9 within the region of deletion.

Animals↗
PubMed1994

DNA diagnosis in oncology.

Our understanding of the genetic changes that transform normal cells into malignant cells is increasing at a remarkable pace. Some of the changes involve detectable cytogenetic aberrations, whereas others are identifiable only at the molecular level. Many of the structural cytogenetic changes have also been defined molecularly because the genes involved have been cloned. Thus, we are approaching the stage in which the DNA obtained from tumor tissue can be analyzed to detect the presence of a series of chromosomal and molecular alterations. These studies provide important information regarding the precise diagnosis of the tumor type as well as prognostic information about the likely response to therapy and survival.

Cell Transformation, Neoplastic↗
PubMed1994

Sequence-independent amplification and labeling of yeast artificial chromosomes for fluorescence in situ hybridization.

We have developed a method that allows reliable construction of high quality FISH probes from yeast artificial chromosomes (YACs) based on the separation of YACs by pulse-field gel electrophoresis and a rapid sequence-independent amplification procedure (SIA). These probes can be used to localize YACs on metaphase chromosomes and also with high efficiency, in interphase nuclei.

Base Sequence↗
PubMed1994

The AML1 and ETO genes in acute myeloid leukemia with a t(8;21).

The translocation between chromosomes 8 and 21, t(8;21)(q22;q22), is the most frequent abnormality seen in approximately 46% of patients with acute myeloid leukemia with French-America-British (FAB)-M2 morphology and an aneuploid karyotype. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO (eight twenty one) on chromosome 8. AML1 has homology to the alpha subunit of the murine polyoma enhancer binding protein, pebp2, and to the segmentation gene, runt, of Drosophila melanogaster. ETO, also called MTG8 (myeloid translocation gene on 8) has no overall homology to known proteins, but it contains two DNA-binding zinc finger motifs and several regions that are proline- and serine-rich. Both AML1 and ETO are thought to be transcription factors because the motifs they contain are found in other transcription factors. Both genes are transcribed from telomere to centromere, and cytogenetic analysis of variant translocations has shown that the critical junction always conserved is on the derivative 8 chromosome. The rearrangement between the two chromosomes results in a fusion gene that contains the 5' region of AML1 including that homologous to runt fused to almost all of ETO. The fusion transcript from the der(8) chromosome is consistently detected in patients with the t(8;21). The translocation can be detected at the molecular level with selected genomic DNA probes from chromosome 21 and from chromosome 8 near the breakpoint in 80-100% of the t(8;21) patients at diagnosis and in relapse, and with reverse transcriptase-polymerase chain reaction (RT-PCR) in all of the patients at diagnosis and in long-term remission. These results indicate that leukemic clones are still circulating in patients who have been in remission for as long as 8 years.

Base Sequence↗
PubMed1994

Correlation between cell morphology and expression of the AML1/ETO chimeric transcript in patients with acute myeloid leukemia without the t(8;21).

The 8;21 chromosomal translocation involves the AML1 gene on chromosome 21 and the ETO gene on chromosome 8 and results in the transcription of a chimeric message. This translocation is most often associated with acute myelogenous leukemia with maturation (AML-M2). The leukemic cells of patients carrying t(8;21) often exhibit several characteristic morphologic features. We identified four cases in which the morphology led us to suspect a t(8;21), but in which this translocation was not observed by cytogenetic analysis. In two of the four cases, an AML1/ETO chimeric fragment was detected by reverse transcription and polymerase chain reaction (RT-PCR), and its sequence was found to be identical to that from patients with a cytogenetically proved t(8;21). Marrow specimens of the four patients lacking the t(8;21) cytogenetically were reviewed retrospectively with regard to seven morphologic features commonly reported to be associated with this translocation, and the results were compared to 13 morphologic controls with the t(8;21). Although none of the 13 controls had all of the characteristic morphologic features, all had at least six, as did the two t(8;21)-negative but RT-PCR-positive patients. The two patients who lacked the t(8;21) and who were RT-PCR-negative showed only three and four of these morphologic features, respectively. Both of the RT-PCR-positive patients had deletions of the long arm of chromosome 9, a common change associated with a t(8;21), supporting our assessment of these patients as having a cytogenetically undetected t(8;21).

Base Sequence↗
PubMed1994

Detection of MLL gene rearrangements in adult acute lymphoblastic leukemia. A Cancer and Leukemia Group B study.

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.

Adolescent↗
PubMed1994

1993 Robert R. deVilliers Lecture. Chromosome translocations: dangerous liaisons.

Rearrangements involving chromosome band 11q23 are very common in acute leukemia, both lymphoblastic and myeloid (monoblastic), and are less common in lymphoma. Although several different genes have been cloned from 11q23 translocation breakpoints, the great majority involve the MLL (myeloid-lymphoid leukemia) 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 8.3kb region which can be detected with a 0.7 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 leukemia with translocations involving 11q23. These translocations break MLL in the same 8.3kb region. In the four breakpoints cloned to date, the translocation has led to a fusion gene on the derivative 11 chromosome with a chimeric 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.

Chromosome Mapping↗
PubMed1993

Rearrangements of the MLL gene in therapy-related acute myeloid leukemia in patients previously treated with agents targeting DNA-topoisomerase II.

Chromosome band 11q23 is frequently involved in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) de novo, as well as in myelodysplastic syndromes (MDS) and lymphoma. Five percent to 15% of patients treated with chemotherapy for a primary neoplasm develop therapy-related AML (t-AML) that may show rearrangements, usually translocations involving band 11q23 or, less often, 21q22. These leukemias develop after a relatively short latent period and often follow the use of drugs that inhibit the activity of DNA-topoisomerase II (topo II). We previously identified a gene, MLL (myeloid-lymphoid leukemia or mixed-lineage leukemia), at 11q23 that is involved in the de novo leukemias. We have studied 17 patients with t-MDS/t-AML, 12 of whom had cytogenetically detectable 11q23 rearrangements. Ten of the 12 t-AML patients had received topo II inhibitors and 9 of these, all with balanced translocations of 11q23, had MLL rearrangements on Southern blot analysis. None of the patients who had not received topo II inhibitors showed an MLL rearrangement. Of the 5 patients lacking 11q23 rearrangements, some of whom had monoblastic features, none had an MLL rearrangement, although 4 had received topo II inhibitors. Our study indicates that the MLL gene rearrangements are similar both in AML that develops de novo and in t-AML. The association of exposure to topo II-reactive chemotherapy with 11q23 rearrangements involving the MLL gene in t-AML suggests that topo II may play a role in the aberrant recombination events that occur in this region both in AML de novo and in t-AML.

Adult↗
PubMed1993

The 3;21 translocation in myelodysplasia results in a fusion transcript between the AML1 gene and the gene for EAP, a highly conserved protein associated with the Epstein-Barr virus small RNA EBER 1.

In the 8;21 translocation, the AML1 gene, located at chromosome band 21q22, is translocated to chromosome 8 (q22), where it is fused to the ETO gene and transcribed as a chimeric gene. AML1 is the human homolog of the recently cloned mouse gene pebp2 alpha B, homologous to the DNA binding alpha subunit of the polyoma enhancer factor pebp2. AML1 is also involved in a translocation with chromosome 3 that is seen in patients with therapy-related acute myeloid leukemia and myelodysplastic syndrome and in chronic myelogenous leukemia in blast crisis. We have isolated a fusion cDNA clone from a t(3;21) library derived from a patient with therapy-related myelodysplastic syndrome; this clone contains sequences from AML1 and from EAP, which we have now localized to band 3q26. EAP has previously been characterized as a highly expressed small nuclear protein of 128 residues (EBER 1) associated with Epstein-Barr virus small RNA. The fusion clone contains the DNA binding 5' part of AML1 that is fused to ETO in the t(8;21) and, in addition, at least one other exon. The translocation replaces the last nine codons of AML1 with the last 96 codons of EAP. The fusion does not maintain the correct reading frame of EAP and may not lead to a functional chimeric protein.

Amino Acid Sequence↗
PubMed1993

Persistence of the 8;21 translocation in patients with acute myeloid leukemia type M2 in long-term remission.

The translocation between chromosomes 8 and 21, t(8;21) (q22;q22), is the most frequent abnormality in acute myeloid leukemia (AML) with French-American-British type M2 (FAB-M2) morphology. The breakpoints in this translocation have been characterized at the molecular level, and the genes involved are AML1 on chromosome 21 and ETO on chromosome 8. The rearrangement of the two chromosomes results in a fusion gene and in the production of a consistent fusion transcript on the der(8) chromosome. We have used oligonucleotide primers derived from both sides of the fusion cDNA junction and reverse transcription-polymerase chain reaction (RT-PCR) to analyze six AML-M2 patients with a t(8;21) during various stages of their disease. Two patients studied at diagnosis and one studied at first relapse are alive off therapy and in continuous complete remission for 83 to 94 months. We have detected the AML/ETO fusion transcript in recent peripheral blood samples from each of them. Three other patients also had a fusion transcript detected after 1 to 4 months in remission. Two of these patients subsequently relapsed and died whereas the third patient is alive and in continuous complete remission 70 months later. Thus, our preliminary data suggest that cells with the translocation are still circulating in t(8;21) patients in long-term remission. This finding raises serious questions regarding the interpretation of positive results obtained only with this technique that may not be suitable to decide appropriate further treatment for patients in clinical remission.

Chromosomes, Human, Pair 21↗
PubMed1993

Heterogeneity of breakpoints of 11q23 rearrangements in hematologic malignancies identified with fluorescence in situ hybridization.

Twenty-four patients whose cells contained a variety of 11q23 rearrangements, including translocations, insertions, and an inversion, were studied using fluorescence in situ hybridization with cosmid, phage, and plasmid probes mapped to 11q22-24. In 17 patients, the breakpoints of the common 11q23 translocations involving chromosomes 4, 6, 9, and 19 as well as some uncommon translocations involving 3q23, 17q25, 10p11, and an insertion 10;11 were all located in the breakpoint cluster region of the MLL gene, regardless of age, phenotype of disease, or involvement of a third chromosome. The breakpoints in 11q23 in the other 7 patients with a t(7;11)(p15;q23), inv(11)(p11q23), t(4;11)(q23;q23), der(5)t(5;11)(q13;q23), ins(10;11)(p11;q23q24), t(11;14)(q23;q11), or t(11;18;11) (p15;q21;q23) were located either centromeric to CD3D or telomeric to THY1. Thus, although most 11q23 rearrangements, involve the same breakpoint cluster region of MLL, there is heterogeneity in the breakpoint in some of the rare rearrangements.

Adolescent↗
PubMed1993

Variability of 11q23 rearrangements in hematopoietic cell lines identified with fluorescence in situ hybridization.

We mapped and ordered 17 cosmid, phage, and plasmid clones to chromosome 11, bands q22-q24, using fluorescence in situ hybridization (FISH). We then analyzed four hematopoietic cell lines with 11q23 rearrangements, Karpas 45, SUP-T13, RC-K8, and Karpas 422, using these probes. The studies showed that the translocation breakpoints of the Karpas 45 and SUP-T13 cell lines, which were derived from T-cell malignancies, were located in the same breakpoint cluster region of the MLL gene as the RS4; 11 cell line and patients with the t(9;11), t(11;19), and t(6;11) described previously. We confirmed that the translocation breakpoint of the RC-K8 cell line was located telomeric to the MLL gene, and found that the derivative 11 chromosome of the Karpas 422 cell line, which had been thought to contain a t(4;11) (q21;q23), was in fact formed through a deletion and an inverted tandem repeat of part of 11q.

Cell Line↗