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Biomedical subjects

Gordon W Dewald

Publications and source records attributed to Gordon W Dewald.

At least 37 records · Page 2Linked to original sources
PubMed2005

Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia.

Deletion of the long arm of chromosome 9, del(9q), is a recurring chromosomal aberration in acute myeloid leukemia (AML) that is frequently associated with t(8;21). The critical gene products affected by del(9q) are unknown but likely cooperate with the AML1/ETO fusion gene created by t(8;21) in leukemogenesis. In 43 AML samples with del(9q), we used high-density microsatellite markers to define the commonly deleted region (CDR) to less than 2.4 Mb. We found no homozygous loss at any locus tested. The CDR contains 7 known genes, FRMD3, UBQLN1, GKAP42, KIF27, HNRPK, SLC28A3, and NTRK2, and 4 novel genes, RASEF, C9orf103, C9orf64, and C9orf76. In addition, TLE1 and TLE4 are adjacent to the CDR. We performed a comprehensive mutational analysis of the coding regions of all these genes. No sequence variations absent in normal controls were seen in more than a single del(9q) AML sample. Expression of 7 of the 10 genes examined was significantly down-regulated in del(19q)AML as compared with the CD34-purified progenitors from normal individuals, a pattern distinct from that seen in AML samples with a normal karyotype. The results of our studies are consistent with a model of tumor suppression mediated by haploinsufficiency of critical genes in del(9q) AML.

Acute Disease↗
PubMed2005

Fluorescent-labeled DNA probes applied to novel biological aspects of B-cell chronic lymphocytic leukemia.

Fluorescent-labeled DNA probes were used to study 52 chronic lymphocytic leukemia (B-CLL) patients for (1) disease progression, (2) angiogenesis genes, (3) T-cell leukemia 1 gene (TCL1), (4) immunoglobulin heavy chain variable region (IGHv) and (5) chromosome 6q. Compared to stable disease, more patients with progressive disease had > or =2 anomalies and a high percentage of neoplastic nuclei. Anomalies of genes for basic fibroblast growth factor, interleukin 4, vascular endothelial growth factor or TCL1 were not detected. Deletions in IGHv occurred in 25% of patients and correlated with IGHv gene expression. Probes for 6q23 detected more deletions in 6q than probes for 6q21.

Adult↗
PubMed2005

Intensified induction chemotherapy in adult acute myeloid leukemia followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation: an Eastern Cooperative Oncology Group trial (E4995).

The feasibility of intensified therapy in adults < 61-years-old with de novo acute myeloid leukemia (AML) was evaluated by adding high-dose cytarabine (HDAC) to conventional induction therapy and in post-remission therapy prior to peripheral blood stem cell transplantation (PBSCT). Patients were treated with conventional induction therapy (daunorubicin days 1-3 and cytarabine days 1-7), followed by HDAC (2 gm/M2) every 12 h ( x 6) on days 8-10. Patients in complete remission (CR) with HLA-matched siblings were assigned to allogeneic PBSCT; the others received two courses of HDAC (3 gm/M2 every 12 h on days 1, 3, and 5) given 1 month apart. Peripheral blood stem cells were then harvested and infused after high-dose chemotherapy. Of 62 eligible, evaluable patients, 47 (76%) achieved CR. The mortality rate was 10% (6 patients); no deaths occurred during the two post-remission courses of HDAC. Fifteen patients were assigned to allogeneic PBSCT and 32 to autologous PBSCT. All surviving patients have been followed for more than 4 years. Including all patients scheduled to receive autoPBSCT in an intent-to-treat analysis, after a median 5-year follow-up the current, non-actuarial, four-year event-free and overall survival was 47% and 47%, respectively. Intensified induction therapy was associated with more toxicity than conventional induction therapy, and the CR rate did not improve. Nevertheless, intensive post-remission therapy was well tolerated, no treatment-related mortality occurred with autologous PBSCT, and disease-free survival and overall survival were lengthy.

Adolescent↗
PubMed2005

Adult B-cell lymphomas with burkitt-like morphology are phenotypically and genotypically heterogeneous with aggressive clinical behavior.

Adult, de novo B-cell lymphomas meeting the WHO morphologic criteria for atypical Burkitt/Burkitt-like lymphoma cause diagnostic difficulty for pathologists because the genetic and clinical characteristics of this group of lymphomas have not been clearly defined. Thirty-one such lymphomas, designated as Burkitt-like lymphomas (BLL), were selected based on morphologic features and evaluated for immunophenotype, MYC and BCL2 status, and clinical features. Nine childhood Burkitt lymphomas (BL) and 87 adult, de novo diffuse large B-cell lymphomas (DLBL) were similarly evaluated for comparison. The BL group demonstrated uniform characteristics: all had Burkitt lymphoma morphology, an identical immunophenotype (positive for CD20, CD10, bcl-6, CD43, and p53; negative for CD138, CD23, bcl-2), high MIB-1 positivity, IGH/MYC translocation, no IGH/BCL2 translocation, and all patients were alive at the last follow-up. The BLL and DLBL groups were heterogeneous. Burkitt-like morphology alone correlated with decreased survival. IGH/MYC or IGL/MYC fusion was identified in 11 of 27 (41%) BLL and 4 of 76 (5%) DLBL and was associated with decreased survival in both groups. MIB-1 positivity did not correlate with morphology, MYC abnormalities, or survival. We propose that adult B-cell lymphomas with BLL morphology are a phenotypically and genetically heterogeneous group of aggressive lymphomas, biologically distinct from childhood BL. Until biologically accurate subgroups within this morphologically defined group are identified, it is appears that both recognition of BLL morphology and direct evaluation for the presence of MYC fusion to immunoglobulin genes are important for identification of adult patients with poorer prognosis than those with DLBL.

Adolescent↗
PubMed2005

Der(6)t(1;6)(q21-23;p21.3): a specific cytogenetic abnormality in myelofibrosis with myeloid metaplasia.

Chromosome anomalies are detected in approximately half of patients with myelofibrosis with myeloid metaplasia (MMM) although none of the most prevalent lesions are specific to the disease. In a prospective cytogenetic study of 81 patients with MMM, we encountered three with an unbalanced translocation between chromosomes 1 and 6 with specific breakpoints; der(6)t(1;6)(q21-23;p21.3). A subsequent Mayo Clinic cytogenetic database search identified 12 patients with this chromosome anomaly among 17 791 consecutive patients. A similar database search from Royal Hallamshire Hospital in Sheffield, UK revealed two additional patients among 8000 cases. The clinical phenotype and survival for each of these 14 patients was typical of MMM. These findings suggested that der(6)t(1;6)(q21-23;p21.3) is a highly specific cytogenetic anomaly that may harbour gene(s) specifically associated with MMM. In a preliminary fluorescence in situ hybridization study, the breakpoints on chromosome 6 in two additional cases were found to be telomeric to the gene for 51 kDa FK506-binding protein (FKBP51).

Adult↗
PubMed2005

Clinical correlates of submicroscopic deletions involving the ABL-BCR translocation region in chronic myeloid leukemia.

Recent reports indicate a prognostically detrimental effect of submicroscopic abl-bcr deletions associated with the break and fusion points of the derivative chromosome 9 [der(9)] in chronic myeloid leukemia (CML). In a retrospective cohort of 92 patients with CML, the incidence of an atypical D-FISH pattern, that is consistent with a der(9) deletion was 20%. Complete clinical information was available in 82 patients and revealed no significant differences between 18 deleted and 64 non-deleted cases in platelet count, circulating blast percentage, spleen size, or karyotype profile at presentation. However, der(9)-deleted patients presented with significantly lower hemoglobin levels and higher leukocyte counts. At a median follow-up of 31 months, the incidence of disease transformation, drug therapy response, and survival were similar between the two groups. These results are contrary to previous reports that suggested inferior survival as well as poor response to alpha interferon therapy in CML patients carrying der(9) deletions.

Antineoplastic Agents↗
PubMed2005

Chronic myeloid leukemia: current application of cytogenetics and molecular testing for diagnosis and treatment.

Chronic myeloid leukemia provides an illustrative disease model for both molecular pathogenesis of cancer and rational drug therapy. Chronic myeloid leukemia is a clonal stem cell disease caused by an acquired somatic mutation that fuses, through chromosomal translocation, the abl and bcr genes on chromosomes 9 and 22, respectively. The bcr/abl gene product is an oncogenic protein that localizes to the cytoskeleton and displays an up-regulated tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and cell survival and consequently cell transformation. Such molecular information on pathogenesis has facilitated accurate diagnosis, the development of pathogenesis-targeted drug therapy, and most recently the application of molecular techniques for monitoring minimal residual disease after successful therapy. These issues are discussed within the context of clinical practice.

Antimetabolites, Antineoplastic↗
PubMed2004

FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia.

A novel oncogenic mutation (FIP1L1-PDGFRA), which results in a constitutively activated platelet-derived growth factor receptor-alpha (PDGFRA), has been invariably associated with a primary eosinophilic disorder. The current study examines both the prevalence and the associated clinicopathologic features of this mutation in a cohort of 89 adult patients presenting with an absolute eosinophil count (AEC) of higher than 1.5 x 10(9)/L. A fluorescence in situ hybridization (FISH)-based strategy was used to detect FIP1L1-PDGFRA in bone marrow cells. None of 8 patients with reactive eosinophilia displayed the abnormality, whereas the incidence of FIP1L1-PDGFRA in the remaining 81 patients with primary eosinophilia was 14% (11 patients). None (0%) of 57 patients with the hypereosinophilic syndrome (HES) but 10 (56%) of 19 patients with systemic mast cell disease associated with eosinophilia (SMCD-eos) carried the specific mutation. The bone marrow mast cell infiltration pattern in FIP1L1-PDGFRA(+) SMCD-eos was distinctly diffuse with loose tumoral aggregates. Treatment with low-dose imatinib (100 mg/d) produced complete and durable responses in all 8 FIP1L1-PDGFRA(+) cases treated. In contrast, only 40% partial response rate was seen in 10 HES cases. FIP1L1-PDGFRA is a relatively infrequent but treatment-relevant mutation in primary eosinophilia that is indicative of an underlying systemic mastocytosis.

Adolescent↗
PubMed2004

A novel tricolor, dual-fusion fluorescence in situ hybridization method to detect BCR/ABL fusion in cells with t(9;22)(q34;q11.2) associated with deletion of DNA on the derivative chromosome 9 in chronic myelocytic leukemia.

Dual-color, dual-fusion fluorescence in situ hybridization (D-FISH) can accurately detect and quantify cells with BCR/ABL fusion in <1% of 500 nuclei in 80% of patients with chronic myelocytic leukemia (CML) and t(9;22)(q34;q11.2). The remaining patients have one of three forms of atypical D-FISH patterns; these patterns have different sensitivities to detect disease. Neoplastic cells with one ABL, one BCR, and one BCR/ABL fusion are particularly problematic, because normal cells with coincidental overlap have the same pattern. For these patients, the normal cutoff for D-FISH is >23%. We tested a new method that incorporates an aqua-labeled probe for the argininosuccinate synthetase (ASS) gene into the conventional BCR/ABL D-FISH probe set. This tricolor D-FISH (TD-FISH) method takes advantage of the aqua-labeled ASS probe to distinguish between neoplastic and normal cells. We used TD-FISH to study 20 normal specimens and 35 specimens from 20 patients with known loss of both BCR and ABL from the derivative chromosome 9. The results show that TD-FISH effectively discriminates between cells with overlapping BCR and ABL signals from cells with true BCR/ABL fusion and improves the ability to quantify minimal residual disease from >23% to >1% of 500 interphase nuclei.

Chromosomes, Human, Pair 22↗
PubMed2004

Prevalence, breakpoint distribution, and clinical correlates of t(5;12).

Among 56,709 cytogenetic studies performed during a 15-year period at the Mayo Clinic, 25 cases of t(5;12) were identified. Among 11 patients with available clinical information, 4 had myelodysplastic syndrome, 2 had acute myelocytic leukemia, 2 had myelofibrosis with myeloid metaplasia (MMM), 2 had atypical chronic myelocytic disorder (ACMD), and 1 had chronic myelomonocytic leukemia (CMMoL). The 5q arm was involved in all patients and the 12p arm in only two patients [ACMD,t(5;12)(q33;p13) and MMM,t(5;12)(q11.2;p11.2)], both of whom had eosinophilia and monocytosis. These two features were present in only two other patients [CMMoL,t(5;12)(q35;q24.1) and ACMD,t(5;12)(q31;q24.1)]. The t(5;12) is a rare, myelocytic-exclusive cytogenetic abnormality with a breakpoint-specific association with eosinophilia or monocytosis.

Anemia, Refractory↗
PubMed2004

Primer on medical genomics. Part XI: Visualizing human chromosomes.

In the past century, various methods to visualize human chromosomes were discovered. Chromosome analyses provide an overall view of the human genome that cannot be achieved with any other approach. The methods to visualize chromosomes include various techniques to produce bands along chromosomes, specialized procedures for specific disorders, and fluorescent-labeled DNA for targeted loci. Cytogenetic methods guide the study of the relationship between chromosome structure and gene function. They also aid in mapping locations of genes and identifying chromosome anomalies associated with medical disorders. The clinical diagnosis, prognosis, and response to treatment can be established for many malignant diseases. Cytogenetic methods provide an important diagnostic tool for clinical practice.

Chromosome Aberrations↗
PubMed2003

CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy.

Imatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFR beta- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFR alpha (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.

Adult↗
PubMed2003

The recurrent IgH translocations are highly associated with nonhyperdiploid variant multiple myeloma.

Aneuploid is ubiquitous in multiple myeloma (MM), and 4 cytogenetic subcategories are recognized: hypodiploid (associated with a shorter survival), pseudodiploid, hyperdiploid, and near-tetraploid MM. The hypodiploid, pseudodiploid, and near-tetraploid karyotypes can be referred to as the nonhyperdiploid MM. Immunoglobulin heavy-chain (IgH) translocations are seen in 60% of patients. We studied the relation between aneuploidy and IgH translocations in MM. Eighty patients with MM and abnormal metaphases were studied by means of interphase fluorescent in situ hybridization (FISH) to detect IgH translocations. We also studied a second cohort of 199 patients (Eastern Cooperative Oncology Group [ECOG]) for IgH translocations, chromosome 13 monosomy/deletions (Delta13), and ploidy by DNA content. Mayo Clinic patients with abnormal karyotypes and FISH-detected IgH translocation were more likely to be nonhyperdiploid (89% versus 39%, P <.0001). Remarkably, 88% of tested patients with hypodiploidy (16 of 18) and 90% of tested patients with tetraploidy (9 of 10) had an IgH translocation. ECOG patients with IgH translocations were more likely to have nonhyperdiploid MM by DNA content (68% versus 21%, P <.001). This association was seen predominantly in patients with recurrent chromosome partners to the IgH translocation (11q13, 4p16, and 16q23). The classification of MM into hyperdiploidy and nonhyperdiploidy is dictated largely by the recurrent (primary) IgH translocations in the latter.

Aneuploidy↗
PubMed2003

Clinical and biologic implications of recurrent genomic aberrations in myeloma.

Nonrandom recurrent chromosomal abnormalities are ubiquitous in multiple myeloma (MM) and include, among others, translocations of the immunoglobulin heavy chain locus (IgH). IgH translocations in MM result in the up-regulation of oncogenes, and include more commonly t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23). Based on the recurrent nature of these translocations and their finding since the early stages of the plasma cell (PC) disorders, we hypothesized that they would confer biologic and clinical variability. In addition, deletions of 13q14 and 17p13 have also been associated with a shortened survival. We used cytoplasmic Ig-enhanced interphase fluorescent in situ hybridization to detect deletions (13q14 and 17p13.1), and translocations involving IgH in 351 patients treated with conventional chemotherapy entered into the Eastern Cooperative Oncology Group clinical trial E9486/9487. Translocations were frequently unbalanced with loss of one of the derivative chromosomes. The presence of t(4; 14)(p16;q32) (n = 42; 26 vs 45 months, P <.001), t(14;16)(q32;q23) (n = 15; 16 vs 41 months, P =.003), - 17p13 (n = 37; 23 vs 44 months, P =.005), and - 13q14 (n = 176; 35 vs 51 months, P =.028) were associated with shorter survival. A stratification of patients into 3 distinct categories allowed for prognostication: poor prognosis group (t(4;14)(p16;q32), t(14; 16)(q32;q23), and - 17p13), intermediate prognosis (- 13q14), and good prognosis group (all others), with median survivals of 24.7, 42.3, and 50.5 months, respectively (P <.001). This molecular cytogenetic classification identifies patients into poor, intermediate, and good risk categories. More importantly it provides further compelling evidence that MM is composed of subgroups of patients categorized according to their underlying genomic aberrations.

Adult↗
PubMed2003

Clonal cytogenetic abnormalities in bone marrow specimens without clear morphologic evidence of dysplasia: a form fruste of myelodysplasia?

Cytogenetic abnormalities suggestive of a myeloid disorder are occasionally observed in the bone marrow (BM) cells of patients with morphologically and immunohistochemically unremarkable marrow aspirates and biopsies. Between 1994 and 2000, 55 such patients were seen at our institution (34 men; median age of 66 years). The indications for BM sampling included unexplained cytopenias (31 patients), staging or follow-up of a lymphoproliferative disorder or a plasma cell dyscrasia (18 patients), or another miscellaneous reason (6 patients). Specific cytogenetic abnormalities included a 20q deletion or monosomy 20 (10 patients), a chromosome 7 deletion (8 patients), +8 (5 patients), del(5q) or a 5q translocation (4 patients), and del(13q) (2 patients). Eleven patients had a complex karyotype. As of January 2002, 23 of the 55 patients were dead; median follow-up for living patients is 20 months. Of the 23 dead patients, 1 died of acute myelogenous leukemia (AML) and 6 of complications related to cytopenias. This study provides support for obtaining cytogenetic studies in patients with unexplained cytopenias if a morphologic explanation for the cytopenias is lacking. Continued follow-up of this heterogeneous cohort and further studies of similar patients will more clearly define the disease processes and prognosis for this constellation of laboratory findings.

Aged↗