Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy.

The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices.

Hutchinson-Gilford progeria syndrome through the lens of transcription.

Lamins are nuclear intermediate filaments. In addition to their structural roles, they are implicated in basic nuclear functions such as chromatin organization, DNA replication, transcription, DNA repair, and cell-cycle progression. Mutations in human LMNA gene cause several diseases termed laminopathies. One of the laminopathic diseases is Hutchinson-Gilford progeria syndrome (HGPS), which is caused by a spontaneous mutation and characterized by premature aging. HGPS phenotypes share certain similarities with several apparently comparable medical conditions, such as aging and atherosclerosis, with the conspicuous absence of neuronal degeneration and cancer rarity during the short lifespan of the patients. Cell lines from HGPS patients are characterized by multiple nuclear defects, which include abnormal morphology, altered histone modification patterns, and increased DNA damage. These cell lines provide insight into the molecular pathways including senescence that require lamins A and B1. Here, we review recent data on HGPS phenotypes through the lens of transcriptional deregulation caused by lack of functional lamin A, progerin accumulation, and lamin B1 silencing.

Cytoplasmic sequestration of wild-type p53 in a patient with therapy-related resistant AML: first report.

p53 inactivation is a key factor in human tumorigenesis and chemotherapy resistance. The traditionally described mechanisms of p53 inactivation in acute myeloid leukemia (AML) include TP53 mutations and abrogation of p53 pathway. Malfunction of wild-type (wt) p53, due to its cytoplasmic mislocalization, has been described, thus far, only in solid tumors. Herein, we present a patient with therapy-related resistant AML, monosomal karyotype, wt TP53, and cytoplasmic sequestration of p53 protein. Proposed mechanisms of p53 mislocalization and their probable clinical and therapeutic implications are discussed. In view of the relative rareness of TP53 mutations in AML, the cytoplasmic sequestration of p53 protein offers an additional inactivating mechanism, which might be more frequent than currently diagnosed. This notion warrants confirmation by prospective studies in large cohorts of patients. We recommend that evaluation of p53 subcellular localization and function should be included in the diagnostic work-up of AML with wt p53.

Nuclear lamins: key regulators of nuclear structure and activities.

The nuclear lamina is a proteinaceous structure located underneath the inner nuclear membrane (INM), where it associates with the peripheral chromatin. It contains lamins and lamin-associated proteins, including many integral proteins of the INM, chromatin modifying proteins, transcriptional repressors and structural proteins. A fraction of lamins is also present in the nucleoplasm, where it forms stable complexes and is associated with specific nucleoplasmic proteins. The lamins and their associated proteins are required for most nuclear activities, mitosis and for linking the nucleoplasm to all major cytoskeletal networks in the cytoplasm. Mutations in nuclear lamins and their associated proteins cause about 20 different diseases that are collectively called laminopathies'. This review concentrates mainly on lamins, their structure and their roles in DNA replication, chromatin organization, adult stem cell differentiation, aging, tumorogenesis and the lamin mutations leading to laminopathic diseases.

Follicular lymphoma with extensive gastrointestinal tract involvement: follow-up by capsule endoscopy.

Follicular lymphoma with gastrointestinal tract involvement is rare. We describe the case of a young woman with follicular lymphoma with multiple nodular lesions involving segments of the proximal jejunum and terminal ileum. The presenting symptom was chronic diarrhea. The diagnosis was made by endoscopy with histologic examination of the mucosal lesions of the proximal and distal small intestine, immunohistochemical staining, and molecular analysis. The initial spread and pattern of the small bowel involvement, as well as treatment response, were evaluated by videocapsule endoscopy. The application of molecular analysis along with immunophenotypic evaluation has made it possible to precisely diagnose follicular lymphoma. In the present case, the use of capsule endoscopy improved the evaluation of the extent of small bowel involvement prior to and following treatment.

The nuclear lamina and its proposed roles in tumorigenesis: projection on the hematologic malignancies and future targeted therapy.

The nuclear lamina, a network of lamin filaments and lamin-associated proteins, is located between the inner nuclear membrane and the peripheral chromatin. The nuclear lamina is involved in numerous nuclear functions including maintaining nuclear shape, determining nuclear positioning, organizing chromatin and regulating the cell cycle, DNA replication, transcription, cell differentiation, apoptosis, and aging. Alterations in the composition of nuclear lamins and their associated proteins are currently emerging as an additional event involved in malignant transformation, tumor propagation and progression, thus identifying potential novel targets for future anti-cancer therapy. Here, we review the current knowledge on lamin expression patterns in cells of hematologic malignancies and give an overview on the roles of the nuclear lamina proteins in heterochromatin organization, apoptosis, and aging with special emphasis on the relevance in cancer development.

Antiphospholipid antibodies may be a new prognostic parameter in aggressive non-Hodgkin's lymphoma.

OBJECTIVES: Patients with malignancies have an increased prevalence of antiphospholipid antibodies (APA). The aim of this study was to determine the prevalence of IgG, IgM, and IgA anticardiolipin antibodies (aCL) and anti-beta-2 glycoprotein I antibodies (anti-beta2-GPI) in patients with non-Hodgkin's lymphoma (NHL), and to investigate their clinical and prognostic significance. METHODS: The study group included 86 patients with NHL. Enzyme-linked immunosorbent assay kits were used to measure the concentrations of aCL and anti-beta2-GPI, and coagulation tests, to measure lupus anticoagulant (LAC) activity. Blood was collected at diagnosis in all patients and at follow-up in 15. Median follow-up time was 1.9 yr. RESULTS: Elevated APA levels were found in 35 patients (41%) at diagnosis: one patient aCL IgG, five patients aCL IgM, five aCL IgA, one anti-beta2-GPI IgG, 14 anti-beta2-GPI IgM, and 19 anti-beta2-GPI IgA; LAC activity was found in three of 67 patients (4.5%). There was no significant correlation between elevated APA levels and patient's age or sex, disease stage or grade, bone marrow involvement, B symptoms, serum lactate dehydrogenase levels, serum beta2 microglobulin levels, International Prognostic Index (IPI) score, performance status, type of treatment, or response to treatment. There was a correlation between elevated APA and absence of extranodal disease (P = 0.045). A strong negative correlation was found between elevated APA at diagnosis and survival time. Two-year survival was 90 +/- 5% for patients without APA at diagnosis compared with 63 +/- 11% for patients with an elevated APA levels (P = 0.0025). APA added to the predictive value of IPI for event-free and overall survival. CONCLUSIONS: APA are elevated in 41% of NHL patients at diagnosis and are correlated with shortened survival. Their level may serve as an independent prognostic variable in aggressive NHL.

Non-transferrin-bound serum iron (NTBI) in megaloblastic anemia: effect of vitamin B(12) treatment.

INTRODUCTION: The abnormalities in iron metabolism associated with megaloblastic anemia are rapidly reversed by B(12) therapy in pernicious anemia (PA). Although non-tranferrin-bound plasma iron (NTBI) was previously shown to be associated with severe iron overload, its origin is unknown. METHODS AND RESULTS: Four patients with PA were studied before and after B(12) treatment. NTBI was measured by a fluorescence-based one-step assay. All patients had very high transferrin saturation, NTBI values ranging from 1.1 to 2.6 micromol/l and normal serum ferritins. B(12) treatment resulted in the disappearance of NTBI and normalization of transferrin saturation within 22-42 h. CONCLUSIONS: The prompt disappearance of NTBI following B(12) therapy implicates catabolic iron derived from ineffective erythropoiesis as the major source of NTBI in untreated PA and possibly in thalassemia major and sideroblastic anemia. Our findings offer further insight into the pathogenesis of NTBI in diseases associated with abnormal erythropoiesis.

Serum CA 125 as a prognostic factor in non-Hodgkin's lymphoma.

Cancer antigen 125 (CA 125) is a glycoprotein expressed in normal tissues originally derived from coelomic epithelia such as peritoneum, pleura, pericardium, fallopian tubes and endometrium. Serum CA 125 levels are elevated in various benign and malignant conditions that involve stimulation of these tissues. Although elevated levels have been reported in patients with non-Hodgkin's lymphoma (NHL), its role as a prognostic factor remained uncertain. In this study, serum CA 125 levels were measured prospectively in 108 consecutive patients with NHL: at diagnosis in 106, in remission in 39 and at relapse in 7. Levels were elevated in 43% at diagnosis. This finding was associated with advanced disease stage, bulky tumors, bone marrow involvement, extranodal disease (in stages III and IV), occurrence of B symptoms, pleural or peritoneal effusions, high serum LDH levels, high serum beta2 microglobulin (beta2-M) levels, elevated International Prognostic Score, poor performance status and partial or no response to treatment. No difference in CA 125 level was found between the indolent and aggressive lymphomas. Serum CA 125 levels at diagnosis had strong association with event-free and overall survival (p = 0.01 and 0.003, respectively), with the patients with increased levels having worse survival. Patients with high CA 125 levels at diagnosis who achieved remission showed a significant decrease in CA 125 levels in remission. In conclusion, CA 125 is not only a reliable marker for staging and assessing tumor activity in NHL, elevated levels are also predictive of decreased survival.

The nuclear lamina and its functions in the nucleus.

The nuclear lamina is a structure near the inner nuclear membrane and the peripheral chromatin. It is composed of lamins, which are also present in the nuclear interior, and lamin-associated proteins. The increasing number of proteins that interact with lamins and the compound interactions between these proteins and chromatin-associated proteins make the nuclear lamina a highly complex but also a very exciting structure. The nuclear lamina is an essential component of metazoan cells. It is involved in most nuclear activities including DNA replication, RNA transcription, nuclear and chromatin organization, cell cycle regulation, cell development and differentiation, nuclear migration, and apoptosis. Specific mutations in nuclear lamina genes cause a wide range of heritable human diseases. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Genetic analyses in Caenorhabditis elegans, Drosophila, and mice show new insights into the functions of the nuclear lamina, and recent structural analyses have begun to unravel the molecular structure and assembly of lamins and their associated proteins.