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J D Rowley

Publications and source records attributed to J D Rowley.

At least 163 records · Page 9Linked to original sources
PubMed1989

Clinical-cytogenetic correlations in myelodysplasia (preleukemia).

Cytogenetic studies detected abnormalities in 107 (43%) of the 247 patients in this series. Some degree of overt clinical progression occurred in 55 patients (22%), this being 29% of those patients with cytogenetic abnormalities and 17% of those with normal chromosomes. The presence and complexity of a clonal cytogenetic abnormality correlated with shorter survival. In each clone category of a complexity classification (simple, complex, very complex), patients with some normal cells appeared to have better survival than those with none. In multiple regression analyses, the prognostic value of chromosomes was independent of (and second in importance to) the FAB type of myelodysplastic syndrome (MDS) whichever chromosome classification was used. Patients with refractory anemia (RA) had the lowest incidence of chromosome abnormalities and no cases were found to have only abnormal cells (AA). A greater proportion of patients with refractory anemia with an excess of blasts (RAEB) and RAEB in transformation (RAEB-t) had clonal abnormalities. Morphology alone is not at present able to distinguish between RA or refractory anemia with ringed sideroblasts and similar disorders that may not be MDS in the strict sense. Demonstration of a clonal cytogenetic abnormality remains a positive indication of the presence of the neoplastic nature of the disease.

Adult↗
PubMed1989

Cytogenetic studies of 21 patients with acute lymphoblastic leukemia in relapse.

Karyotypes of 21 patients, originally entered into the Third International Workshop on Chromosomes in Leukemia (3IWCL), were investigated in first, second and/or subsequent relapses. Karyotypes at diagnosis were related to the relapses in the following ways: normal to normal (N-N) (five cases); abnormal to normal (A-N) (two cases); abnormal to abnormal with no change (A-A) (five cases); abnormal to abnormal with clonal evolution (A-A+) (eight cases); and normal to abnormal (N-A) (one case). The A-A group comprised two each of t(4;11) and t(9;22) cases and one pseudodiploid case; included in this group were the only two patients who did not receive intensive treatment. Both A-N cases had been pseudodiploid at diagnosis. Clonal evolution A-A+ occurred in patients who had had 47-49 chromosomes or pseudodiploidy at diagnosis and was mainly due to the addition of structural change. The additional abnormalities were different in each case. The only de novo appearance of a clone (N-A) was in host cells in relapse following bone marrow transplantation. Clonal evolution occurred in patients who had been intensively treated and who relapsed late; the median time from diagnosis to relapse studied for the A-A group was 6 months and for the A-A+ group was 24 months. Survival following relapse was shorter for patients who had had a clonal abnormality at any time (median 10 months) than for those with no abnormality at diagnosis or in relapse (median 26 months).

Adolescent↗
PubMed1989

Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia.

To evaluate the importance of pretreatment karyotype in predicting long-term outcome in acute lymphoblastic leukemia (ALL), we performed a follow-up study of the 329 patients from the Third International Workshop on Chromosomes in Leukemia. Living patients have now been followed a minimum of 6 years. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, rearrangements involving 8q24, t(4;11), 14q+, 6q-] or, in the remaining cases, modal number (less than 46, 46, 47-50, greater than 50). As previously reported for achievement and duration of complete remission, and overall survival, disease-free survival differed significantly (p less than 0.001) among chromosome groups for both adults and children. Among children, karyotype was an independent prognostic factor for predicting disease-free survival. Because of the long follow-up, we now have been able to utilize statistical models to estimate the percentage of patients cured, according to karyotype alone and combined with other risk factors. Adults with the highest likelihood of cure (21-33%) were those patients with FAB-L1, a leukocyte count of 50,000/microliters or less, and one of the following chromosome groups: greater than 50, 47-50, 6q-, or normal. In children these same characteristics were associated with the highest percentage of cure (58-71% cured). In addition, we identified several groups of children with less than 15% chance of cure who clearly need to be treated as high-risk patients at diagnosis. Future studies of patients who have received risk-adapted therapy based on these chromosome data are needed to determine if more intensive treatment will improve the outlook of patients with cytogenetically unfavorable types of ALL.

Adult↗
PubMed1989

Interleukin-4 and interleukin-5 map to human chromosome 5 in a region encoding growth factors and receptors and are deleted in myeloid leukemias with a del(5q).

Interleukin-4 (IL-4) is a potent mediator of growth and differentiation of cells of several hematopoietic lineages. Interleukin-5 (IL-5) is a lineage-specific hematopoietic growth factor that stimulates the production of eosinophils and eosinophil colonies from normal human bone marrow cells. By using somatic cell hybrids and in situ chromosomal hybridization, we localized the IL-4 and IL-5 genes to human chromosome 5 at bands q23-31, a chromosomal region that is frequently deleted [del(5q)] in patients with myeloid disorders. By in situ hybridization, the IL-4 and IL-5 genes were found to be deleted in the 5q- chromosome of four patients with refractory anemia (RA) or therapy-related acute nonlymphocytic leukemia (t-ANLL), who had a del(5q). Thus a small segment of chromosome 5 contains IL-4, IL-5, IL-3, and GM-CSF as well as other genes such as CD14 and EGR1. Our findings that each of these genes was deleted in the 5q- chromosome suggest that loss of function of one or more of these genes may play an important role in the pathogenesis of hematologic disorders associated with a del(5q).

Chromosome Deletion↗
PubMed1989

An (8;14)(q24;q11) translocation involving the T-cell receptor alpha-chain gene and the MYC oncogene 3' region in a B-cell lymphoma.

We describe a t(8;14)(q24;q11) involving the T-cell receptor alpha-chain gene (TCRA) and the 3' region of the MYC protooncogene in a B-cell lymphoma. The B-cell origin of this tumor was determined by its histological architecture, by immunophenotypic analysis, and by Southern analysis of immunoglobulin gene rearrangements. An identical fragment encompassing the translocation breakpoint junction was detected through Southern analysis using both a TCRAJ and a MYC probe. The other alleles at the TCRAJ and MYC loci were in the germline configuration. Restriction enzyme and nucleotide sequencing analyses revealed that the breakpoint junction on chromosome 8 lies approximately 700 base pairs (bp) downstream of the 3' end of the third MYC exon; on chromosome 14, the break is located 12.6 kilobases (kb) downstream of the 3' end of the C delta fourth exon. A heptamer-like consensus sequence on chromosome 14 adjacent to the translocation breakpoint implies the involvement of recombinase activity. However, no consensus sequences were found on chromosome 8 within 140 bp in either direction from the breakpoint. It is possible that this translocation involving MYC occurred during an attempt at an inappropriate rearrangement of the TCRA locus in a cell of B-cell lineage.

Base Sequence↗
PubMed1989

Chromosomal sensitivity of lymphocytes from individuals with therapy-related acute nonlymphocytic leukemia.

A small fraction of those individuals exposed to cytotoxic chemotherapy or radiation for the treatment of a primary malignant disease will develop a second malignancy some time later. Although exposure to the cytotoxic agents is believed to be the causative factor, the reason only certain individuals develop the second malignancy is unknown. Some studies have suggested that these individuals might be predisposed to cancer because of an inherent sensitivity to the alkylating agents used in cancer therapy. We have reported that these individuals with therapy-related acute nonlymphocytic leukemia (t-ANLL) have reduced endogenous levels of the repair protein O6-alkylguanine alkyltransferase (AGT). To further investigate the etiology of this disease, alkylation-induced sister-chromatid exchange (SCE) formation in individuals who developed second malignancies, was compared to other patient groups and normal controls. Peripheral blood lymphocytes from patients with (1) t-ANLL, (2) primary forms of acute nonlymphocytic leukemia (ANLL de novo), (3) patients with primary malignancies at risk of developing secondary disease, and (4) unexposed, healthy controls were treated in vitro with N-methyl-N'-nitro-nitrosoguanidine or mitomycin C. Baseline and mutagen-induced frequencies of SCEs were determined. These studies failed to detect any increased sensitivity in those patients who developed second malignancies as compared to controls or patients with de novo forms of the same disease. Also, no correlation between sensitivity to the alkylating agent N-methyl-N'-nitro-nitrosoguanidine and endogenous levels of the AGT repair protein was found. These results suggest that t-ANLL patients are not sensitive to SCE induction by either MNNG or MMC.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1989

Der(5)t(5;7)(q11.2;p11.2): a new recurring abnormality in malignant myeloid disorders.

Complete or partial monosomy for the long arm of chromosomes 5 and/or 7 is frequently observed in malignant cells from patients with a therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute nonlymphocytic leukemia (t-ANLL). Partial monosomy is usually the result of a chromosomal deletion; however, unbalanced translocations have also been observed. We have identified one such translocation in three patients who had either t-ANLL or a primary MDS. The genetic consequences of this translocation [-5,-7,+der(5)t(5;7)(q11.2;p11.2)] are partial monosomy for the long arm of chromosome 5 and complete monosomy for the long arm of chromosome 7. Thus, this rearrangement may represent a new, recurring abnormality that is associated with malignant myeloid disorders.

Aged↗
PubMed1989

Unexpected heterogeneity of BCR-ABL fusion mRNA detected by polymerase chain reaction in Philadelphia chromosome-positive acute lymphoblastic leukemia.

The Philadelphia (Ph1) chromosome results in a fusion of portions of the BCR gene from chromosome 22 and the ABL gene from chromosome 9, producing a chimeric BCR-ABL mRNA and protein. In lymphoblastic leukemias, there are two molecular subtypes of the Ph1 chromosome, one with a rearrangement of the breakpoint cluster region (bcr) of the BCR gene, producing the same 8.5-kilobase BCR-ABL fusion mRNA seen in chronic myelogenous leukemia (CML), and the other, without a bcr rearrangement, producing a 7.0-kilobase BCR-ABL fusion mRNA that is seen only in acute lymphoblastic leukemia (ALL). We studied the molecular subtype of the Ph1 chromosome in 11 cases of Ph1-positive ALL, including 2 with a previous diagnosis of CML, using a sensitive method to analyze the mRNA species based on the polymerase chain reaction (PCR). We observed unexpected heterogeneity in BCR-ABL mRNA in this population; in particular, 1 of 6 bcr-rearranged cases and 1 of 5 bcr-unrearranged cases contained none of the known fusion mRNA species, while 1 of the bcr-rearranged cases contained both. This latter case is particularly interesting because it suggests that the acquisition of an additional BCR-ABL fusion species may be a mechanism of disease progression. We conclude that the PCR gives additional information about the Ph1 chromosome gene products that cannot be obtained by genomic analysis, but that it cannot be used as the sole means of detection of this chromosomal abnormality in ALL because of the high incidence of false negative results.

Blotting, Southern↗
PubMed1989

Clinicopathologic manifestations and breakpoints of the t(3;5) in patients with acute nonlymphocytic leukemia.

Acquired chromosomal rearrangements in acute nonlymphocytic leukemia (ANLL) have been linked to specific clinicopathologic features that suggest new disease subtypes. In this collaborative study, we report five patients with ANLL and a t(3;5) in their leukemic cells. At diagnosis, four of the patients had a t(3;5) as their sole karyotypic anomaly; the remaining patient had additional structural and numerical abnormalities. Careful cytogenetic analysis indicated that the breakpoints of this rearrangement are 3q25.1 and 5q34, in contrast to the various breakpoints reported in earlier studies (3q21----3q25 and 5q31----5q35). The karyotypic, morphologic, and clinical characteristics of this group, as well as those of 14 previously reported patients with the t(3;5), were compared to identify any features that might warrant consideration of a specific syndrome. The available information indicates a worldwide distribution and a nearly equal male:female ratio for patients with this translocation. The median age of the group, 37 years, was younger than that of all patients with ANLL, 49 years. A preceding myelodysplastic syndrome was observed in three patients. The limited numbers of observations on leukocyte count, hemoglobin level, and platelet count precluded meaningful comparison with data for ANLL patients in general. Although each FAB morphologic subtype, except M3, occurred in patients with a t(3;5), the frequency of M6 was much greater than expected. Bone marrows from each of the five patients we report showed increased numbers of megakaryocytes; trilineage dysplasia was observed in the marrow of each of the four patients for whom it could be assessed. Taken together, these findings suggest that the t(3;5) may affect cells capable of differentiation into multiple lineages.

Adolescent↗
PubMed1989

Chromosome abnormalities in B cell chronic lymphocytic leukemia and their clinical correlations.

Cytogenetic analysis was successfully performed on 31 of 40 patients with chronic B cell leukemia. Clonal abnormalities were seen in 16 patients using various culture methods. Fourteen of these had unstimulated cultures established of which 13 had the clonal abnormality. Trisomy 12 was observed in seven patients while a 14q32 translocation was present in four. Race, age, hemoglobin, WBC, percentage of lymphocytes and prolymphocytes in BM and PB, platelets, Smig, lymph node, spleen, liver, pattern of bone marrow infiltration, therapy free interval, and overall survival were all compared. Significant correlations between the presence of clonal abnormalities and prior therapy (p less than 0.005) and an increase in prolymphocytes in bone marrow (p = 0.05) and/or peripheral blood (p = 0.0014) were observed.

Adult↗
PubMed1988

A recurring chromosome rearrangement, dic(16;22), in acute nonlymphocytic leukemia.

A dicentric chromosome, dic(16;22), resulting in the loss of 16q and 22p was seen in bone marrow cells from two patients with acute myelomonocytic leukemia and one patient with a therapy-related myelodysplastic syndrome that evolved to leukemia. Review of the clinical findings and of the bone marrow morphology failed to reveal any distinctive features in common among these patients. The dic(16;22) may be a new, rare, recurring abnormality associated with malignant myeloid disorders.

Aged↗
PubMed1988

Variant translocations (9;11): identification of the critical genetic rearrangement.

The t(9;11)(p22;q23) is a recurring abnormality in acute nonlymphocytic leukemia. The analysis of complex 9;11 translocations will aid in the identification of the conserved chromosomal junction or the critical genetic alteration created by the rearrangement; however, variant translocations involving chromosomes #9 and #11 have not been reported. We have identified such variants in two patients who had acute myelomonocytic leukemia and acute monocytic leukemia, characterized by a t(9;11;18)(p22;q23;q12) and a t(9;11;13)(p22;q23;q34), respectively. The conserved junction resulting from these rearrangements is created by the translocation of chromosomal material from 9p to 11q.

Aged↗
PubMed1988

Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines.

The loss of bands p21-22 from one chromosome 9 homologue as a consequence of a deletion of the short arm [del(9p)], unbalanced translocation, or monosomy 9 is frequently observed in the malignant cells of patients with lymphoid neoplasias, including acute lymphoblastic leukemia and non-Hodgkin lymphoma. The alpha- and beta 1-interferon genes have been assigned to this chromosome region (9p21-22). We now present evidence of the homozygous deletion of the interferon genes in neoplastic hematopoietic cell lines and primary leukemia cells in the presence or absence of chromosomal deletions that are detectable at the level of the light microscope. In these cell lines, the deletion of the interferon genes is accompanied by a deficiency of 5'-methylthioadenosine phosphorylase (EC 2.4.2.28), an enzyme of purine metabolism. These homozygous deletions may be associated with the loss of a tumor-suppressor gene that is involved in the development of these neoplasias. The relevant genes may be either the interferon genes themselves or a gene that has a tumor-suppressor function and is closely linked to them.

Chromosome Deletion↗
PubMed1988

Molecular cloning, sequencing, and mapping of EGR2, a human early growth response gene encoding a protein with "zinc-binding finger" structure.

Early growth response gene-1 (Egr-1) is a mouse gene displaying fos-like induction kinetics in diverse cell types following mitogenic stimulation. Egr-1 encodes a protein with "zinc-binding finger" structure. Zinc fingers are a protein structural motif that serve as DNA-binding domains in several transcriptional regulatory proteins. Using low-stringency hybridization with an Egr-1 cDNA probe, we identified a distinct human cDNA (designated EGR2 for early growth response gene-2), which is coregulated with EGR1 by fibroblast and lymphocyte mitogens; however, several stimuli that induce Egr-1 mRNA in PC12 (rat pheochromocytoma) cells do not induce Egr-2 mRNA. The cDNA sequence predicts a protein of 406 amino acids, including three tandem zinc fingers of the Cys2-His2 class. Strikingly, the deduced amino acid sequences of human EGR2 and mouse Egr-1 are 92% identical in the zinc finger region but show no similarity elsewhere. EGR2 maps to human chromosome 10 at bands q21-22. Structure-function analysis of EGR2 and EGR1 proteins should provide insight into the mechanisms linking signal transduction and transcriptional regulation of gene expression.

Amino Acid Sequence↗