187 research outputs found
Molecular cytogenetic characterization of a critical region in bands 7q35-q36 commonly deleted in malignant myeloid disorders
No full textLoss of chromosome 7 (-7) or deletion of the long arm (7q-) are recurring chromosome abnormalities in myeloid leukemias. The association of -7/7q- with myeloid leukemia suggests that these regions contain novel tumor suppressor gene(s), whose loss of function contribute to leukemic transformation or tumor progression. Based on chromosome banding analysis, two critical regions have been identified, one in band q22 and another in bands q32-q35. Presently there are no data available on the molecular delineation of the distal critical region. In this study we analyzed bone marrow and blood samples from 13 patients with myeloid leukemia (de novo myelodysplastic syndrome [MDS], n = 3; de novo acute myeloid leukemia [AML], n = 9; therapy-related (t-) AML, n = 1) which, on chromosome banding analysis, exhibited deletions (n = 12) or in one case a balanced translocation involving bands 7q31-qter using fluorescence in situ hybridization (FISH). As probes we used representative clones from a contig map of yeast artificial chromosome (YAC) clones that spans chromosome bands 7q31.1-qter. In the 12 cases with loss of 7q material, we identified a commonly deleted region of approximately 4 to 5 megabasepairs in size encompassing the distal part of 7q35 and the proximal part of 7q36. Furthermore, the breakpoint of the reciprocal translocation from the patient with t-AML was localized to a 1,300-kb sized YAC clone that maps to the proximal boundary of the commonly deleted region. Interestingly, in this case both homologs of chromosome 7 were affected: one was lost (-7) and the second exhibited the t(7q35). The identification and delineation of translocation and deletion breakpoints provides the first step toward the identification of the gene(s) involved in the pathogenesis of 7q35-q36 aberrations in myeloid disorders
Dissecting Genetic and Phenotypic Heterogeneity to Map Molecular Phylogenies and Deliver Personalized Outcome and Treatment Predictions in AML
No full textFor many years, clinical management of Acute Myeloid Leukemia (AML) has relied on patient classification into molecular groups, mostly defined by fusion genes. Recent insights of AML genomes have uncovered extended heterogeneity implicating >100 recurrently mutated genes, many of which are infrequently mutated. In each patient, multiple mutations are present defining unique genetic and clonal constellations. This genetic diversity significantly complicates the translation of molecular findings into routine clinical practice.
We present our full analysis on the genomic characterization of 1540 AML patients enrolled in clinical trials of the German-Austrian AML Study Group. Together with cytogenetic profiling we map 5234 pathogenic lesions across 77 genomic loci. Amongst these, we characterise a cluster of hotspot mutations in the MYC oncogene. Overall we find ≥1 driver mutation in 96% patients, and ≥2 in 85%. The earliest mutations in AML evolution implicate genes mutated in age-related clonal hematopoiesis (DNMT3A, ASXL1, TET2) or fusion genes, followed by ordered acquisition of mutations in transcription, chromatin or splicing regulators. RTK/RAS mutations frequently represent late events with evidence of parallel evolution in 14% of AML.
We formally model genomic structure and find that AML is subdivided in at least 11 molecular and clinically distinct classes defined by t(15;17), t(8;21), inv(16)/t(16;16), t(6;9), inv(3)/t(3;3), AML defined by MLL- rearrangements, CEBPAbi-allelic, NPM1, TP53/complex karyotype, AML with chromatin/splicing factor mutations, and provisionally AML with <3 aneuploidies. ~87% of patients with acquired mutations are molecularly classified. Each class is defined by a distinct subset of genetic lesions, with evidence of preferred order in mutation acquisition, thus guiding future development of minimal residual disease and combination therapy protocols.
19% (n=291) of patients were classified in the chromatin/spliceosome class. In this group, mutations in splicing factor genes and/or RUNX1 cluster with mutations in chromatin modifiers (ASXL1, EZH2, STAG2, MLLPTD). Patients in this group mostly represented Intermediate risk AML (ELN recommendations), were older, with lower WBC/blasts, inferior response rates to induction chemotherapy, poor long-term clinical outlook, higher rates of secondary AML and MDS-related morphology.
Compared to classes defined by fusion genes, classes defined by genes are considerably more complex. We explore whether variability of clinical response (complete remission, relapse, relapse related mortality and overall survival) is at least in part accounted for by the extended genomic landscape. We find that the recurrent secondary and tertiary genotypes (often implicating rare genes/mutation-hotspots) markedly redefine clinical response and long-term curability beyond those predicted by single classifier lesions. To this effect, we apply global statistical models to calculate the contributions of genomic variables to overall risk whilst taking into account demographic, diagnostic and treatment factors. We find that gene-by-gene interactions are associated with additive as well as epistatic effects to patients risk, and contribute ~10% of relapse related mortality risk.
We build prognostication models tailored to individual patients molecular, demographic and clinical variables at time of diagnosis and deliver more accurate risk predictions. For example, on the basis of the composite genomic and clinical profiles subsets of patients categorized as Favorable/Intermediate risk AML show risk estimates associated with adverse prognosis. Such patients are evaluated for therapeutic protocol selection tailored to higher risk groups (transplant at first CR instead of relapse), and ascertained for overall survival benefit. We apply same approaches for high-risk patients associated with favorable profiles and collectively deliver a paradigm of personally tailored risk assessment coupled with appropriate selection of therapeutic intervention.
Taken together comprehensive genome profiling shows that genetic heterogeneity in AML is not random. Characterization of the extended genetic framework beyond single classifier lesions, informs future strategies for personalized prognostication, minimal residual disease monitoring and combination therapy protocols
Acute myeloid leukemia with deletion 9q is associated with CEBPA loss-of-function mutations.
No full textAcute myeloid leukemia with deletion 9q is associated with CEBPA loss-of-function mutations.
No full textAcute myeloid leukemia with deletion 9q within a noncomplex karyotype is associated with CEBPA loss-of-function mutations
No full textTo assess the prevalence of mutations in the CEBPA gene, which encodes the myeloid transcription factor CEBPA in specific cytogenetic subgroups, we initially studied 125 patients with acute myeloid leukemia (AML). Five of the eight patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of CEBPA function. Consequently, 41 additional del(9q) cases were analyzed; nine had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) in a noncomplex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) in a complex karyotype (n = 7) or together with a t(8;21) (n = 10) demonstrated mutant CEBPA. We have shown for the first time that AML with del(9q) in the context of a noncomplex karyotype is strongly associated with CEBPA loss-of-function mutations. Loss of a critical segment of 9q, most likely in 9q22, and disruption of CEBPA function possibly cooperate in the pathogenesis of del(9q) AML. (C) 2005 Wiley-Liss, Inc.NCI NIH HHS [CA 10114 0, CA 16058, CA 77658
Developing Country Debt and Economic Performance, Volume 3: Country Studies - Indonesia, Korea, Philippines, Turkey
No full textDefining disease modification in myelofibrosis in the era of targeted therapy
No full textThe development of targeted therapies for the treatment of myelofibrosis highlights a unique issue in a field that has historically relied on symptom relief, rather than survival benefit or modification of disease course, as key response criteria. There is, therefore, a need to understand what constitutes disease modification of myelofibrosis to advance appropriate drug development and therapeutic pathways. Here, the authors discuss recent clinical trial data of agents in development and dissect the potential for novel end points to act as disease modifying parameters. Using the rationale garnered from latest clinical and scientific evidence, the authors propose a definition of disease modification in myelofibrosis. With improved overall survival a critical outcome, alongside the normalization of hematopoiesis and improvement in bone marrow fibrosis, there will be an increasing need for surrogate measures of survival for use in the early stages of trials. As such, the design of future clinical trials will require re-evaluation and updating to incorporate informative parameters and end points with standardized definitions and methodologies
The EHA research roadmap: malignant myeloid diseases
No full textIn 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy
Trade policy, industrial policy, and the exchange rate
No full text노트 : - Volume Title: Developing country debt and economic performance, Volume 3: country studies - Indonesia, Korea, Philippines, Turke
Prognostic impact of prevalent chronic lymphocytic leukemia stereotyped subsets: Analysis within prospective clinical trials of the German CLL Study Group
No full textAlmost one-third of all patients with chronic lymphocytic leukemia (CLL) express stereotyped B-cell receptor immunoglobulins (BcR IG) and can be assigned to distinct subsets, each with a particular BcR IG. The largest stereotyped subsets are #1, #2, #4 and #8, associated with specific clinico-biological characteristics and outcomes in retrospective studies. We assessed the associations and prognostic value of these BcR IG in prospective multicenter clinical trials reflective of two different clinical situations: (i) early-stage patients ('watch and wait' arm of the CLL1 trial) (n=592); (ii) patients in need of treatment, enrolled in three phase III trials (CLL8, CLL10, CLL11), treated with different chemo-immunotherapies (n=1,861). Subset #1 was associated with del(11q), higher CLL International Prognostic Index (CLL-IPI) scores and similar clinical course to CLL with unmutated immunoglobulin heavy variable (IGHV) genes (U-CLL) in both early and advanced stage groups. IGHV-mutated (M-CLL) subset #2 cases had shorter time-to-first-treatment (TTFT) versus other M-CLL cases in the early-stage cohort (hazard ratio [HR]: 4.2, confidence interval [CI]: 2-8.6, P<0.001), and shorter time-to-next-treatment (TTNT) in the advancedstage cohort (HR: 2, CI: 1.2-3.3, P=0.005). M-CLL subset #4 was associated with lower CLL-IPI scores and younger age at diagnosis; in both cohorts, these patients showed a trend towards better outcomes versus other MCLL. U-CLL subset #8 was associated with trisomy 12. Overall, this study shows that major stereotyped subsets have distinctive characteristics. For the first time in prospective multicenter clinical trials, subset #2 appeared as an independent prognostic factor for earlier TTFT and TTNT and should be proposed for risk stratification of patients
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