National Cancer Institute®
Last Modified: November 21, 2001
UI - 20480737
AU - Trisolini R; Lazzari Agli L; Poletti V
TI - Bronchiolocentric pulmonary involvement due to chronic lymphocytic leukemia.
SO - Haematologica 2000 Oct;85(10):1097
AD - Dipartimento di Malattie del Torace, Azienda USL Citt di Bologna, Italy.
UI - 21240485
AU - Vu UE; Pavletic ZS; Wang X; Joshi SS
TI - Increased cytotoxicity against B-chronic lymphocytic leukemia by cellular manipulations: potentials for therapeutic use.
SO - Leuk Lymphoma 2000 Nov;39(5-6):573-82
AD - Department of Cell Biology and Anatomy, University of Nebraska Medical Center Omaha, Nebraska 68198-6395, USA.
B-cell chronic lymphocytic leukemia (CLL) is characterized by profound immune dysfunction and a marked resistance to apoptosis. Understanding the cellular biology of immune effector cells from CLL patients as well as leukemic target cells is essential to developing immune mediated therapeutic strategies for CLL. In this study, an immortal CLL cell line called WSU-CLL has been used to study the characteristics of B-cell CLL as a tumor target for natural killer (NK), activated natural killer, and lymphokine activated killer (LAK) cells. The WSU-CLL cells were significantly less (p<0.001) susceptible to NK cell mediated cytotoxicity compared to K562, a standard tumor target cell line. In vitro activation of effector cells with either short term, low dose IL-2 or long term, high dose IL-2 significantly increased the susceptibility of CLL cells for cell mediated killing. The addition of CD1a+/CD3-/CD4+/CD80+/CD83+ dendritic cells derived from human umbilical cord blood increased the cytotoxicity of LAK cells against WSU-CLL. There is an increased expression of Bcl-2 and decreased expression of Fas on WSU-CLL cells as determined by RT-PCR techniques indicating possible roles for these genes in exerting resistance to immune cell mediated lysis. When Bcl-2 expression was downregulated in WSU-CLL cells using gene specific antisense oligonucleotides, the susceptibility of WSU-CLL cells to the cytotoxicity of chemotherapeutic agent Fludarabine was increased. Thus, our results suggest that in vitro activation with cytokines, addition of accessory cell populations such as dendritic cells and/or manipulation of key gene expression i.e. down regulation of Bcl-2 might be potential strategies to increase the antitumor cytotoxicity against CLL cells.
UI - 21240491
AU - Evans HL; Polski JM; Deshpande V; Dunphy CH
TI - CD5+ true SLL/CLL with plasmacytic differentiation and an unusual 1p36 translocation: case report and review of the literature.
SO - Leuk Lymphoma 2000 Nov;39(5-6):625-32
AD - Department of Pathology, Division of Hematopathology, St Louis University School of Medicine, St Louis, MO 63104, USA. email@example.com
Lymphoplasmacytic lymphoma (LPL) and small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL)are distinct clinicopathologic entities. Although some cases of SLL/CLL may show plasmacytic differentiation and be associated with monoclonal immunoglobulin in serum, such cases appear to be very rare, and if plasma cell differentiation were marked, differentiation of SLL/CLL from LPL could be difficult. We report a rare case of true CD5-positive small lymphocytic lymphoma/chronic lymphocytic leukemia with unequivocal plasmacytic differentiation. This case also showed an abnormality of chromosome 1p36 not previously described in small lymphocytic lymphoma/chronic lymphocytic leukemia.
UI - 21109943
AU - Woodlock TJ; Bethlendy G; Segel GB
TI - Prohibitin expression is increased in phorbol ester-treated chronic leukemic B-lymphocytes.
SO - Blood Cells Mol Dis 2001 Jan-Feb;27(1):27-34
AD - Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
Chronic lymphocytic leukemia (CLL) is characterized by the gradual accumulation of immature B-lymphocytes. CLL B-lymphocytes mature to a plasmacytoid phenotype when treated in vitro with phorbol esters. CLL B-cell apparent maturation is associated with altered expression of specific plasma membrane and mitochondrial proteins including heightened expression of a 30-kDa heat shock protein 60 (hsp60) analog. During our efforts to further characterize this hsp60 analog by mass spectrometry, we detected the mitochondrial protein prohibitin in phorbol-ester-matured CLL B-lymphocytes. Prohibitin modulates cell proliferation and inhibits cell cycle traverse in several systems, although few data are available for lymphocytes. A twofold increase in prohibitin concentration was observed in phorbol-ester-matured compared to resting CLL B-cells as determined by quantitative Western immunoblot analysis. A similar increase in prohibitin was observed in phorbol-ester-treated normal human B-lymphocyte populations. An antisense oligonucleotide complementary to the 5' coding region of the prohibitin gene blunted the increase in prohibitin protein in phorbol-ester-treated CLL B-cells by 42%. These data suggest that increased prohibitin expression is associated with and may facilitate B-cell maturation. Copyright 2001 Academic Press.
UI - 21360492
AU - Itala M
TI - [Current treatment of chronic lymphocytic leukemia]
SO - Duodecim 1997;113(11):1015-22
AD - Department of Internal Medicine, Turku University Central Hospital, Turku, Finland.
UI - 21379340
AU - Matutes E; Polliack A
TI - Morphological and immunophenotypic features of chronic lymphocytic leukemia.
SO - Rev Clin Exp Hematol 2000 Mar;4(1):22-47
AD - Academic Department of Haematology and Cytogenetics, Royal Marsden Hospital and Institute of Cancer Research, Fulham Road, London, SW3 6JJ, UK. firstname.lastname@example.org
In this review, we summarize the morphological features and immunophenotypic profile of chronic lymphocytic leukemia (CLL) cells, discuss the value of these investigations as front line diagnostic tests, and emphasize their correlation with the clinical features, disease progression, molecular genetics and pathogenesis of CLL. In CLL, the morphology of the circulating cells is characteristic and typical in the majority of cases. However, 15% of patients, either at diagnosis or during the course of the disease, show atypical morphology reflected by either (1) an increased (> 10%) number of circulating prolymphocytes, designated CLL/PL, or (2) an increased (> 15%) number of circulating lymphoplasmacytic and cleaved cells, designated 'atypical' CLL. There is strong evidence of a close association between atypical morphology (CLL/PL) and atypical (CLL) and clinical features, e.g. disease progression, advanced stage and survival, molecular genetics, particularly trisomy 12, but also the rare cases with t(11;14) or t(14;19), p53 abnormalities, unmutated immunoglobulin (Ig) VH genes and origin of the cell (naive, pregerminal center cell). CLL cells have a distinct immunological repertoire different from that of other lymphoproliferative disorders. The typical CLL phenotype is CD5+, CD23+, FMC7-, weak expression of surface Ig (sIg) and weak or absent expression of membrane CD22 and CD79b. The latter marker identifies an extracellular epitope of the B-cell receptor (BCR) beta chain and its weak or absent expression in CLL may derive from the expression of a truncated form. This, together with the low expression of CD22, might explain the abnormal signal transduction of CLL cells similar to that of anergic B lymphocytes. Because no single marker is specific for CLL, a composite phenotype considering this set of 5 or 6 markers compounded into a scoring system helps to distinguish CLL from the other B-cell malignancies. Immunophenotypic analysis has also been shown to be useful for minimal residual disease detection and adds valuable prognostic information because the expression of certain markers, such as FMC7 or CD38, seems to be associated with a poor outcome. In addition, CLL cells express a variety of Bcl-2 family proteins with a profile that favors inhibition of apoptosis which, together with the interaction with microenvironmental (e.g. stromal) cells and the release of cytokines, explains the long life span and subsequent accumulation of CLL cells in various organs. Despite controversies relating to the expression of adhesion molecules (selectins and integrins) in CLL cells, it appears that some of these molecules do play a role in the pathogenesis, biology and clinical patterns of the disease. In conclusion, morphology and immunophenotype are the two essential investigations, which must be carried out in all cases of CLL. Both provide relevant information in terms of diagnosis, course of the disease, prognosis and pathogenesis.
UI - 21379341
AU - Stilgenbauer S; Lichter P; Dohner H
TI - Genetic features of B-cell chronic lymphocytic leukemia.
SO - Rev Clin Exp Hematol 2000 Mar;4(1):48-72
AD - Department of Internal Medicine III, University of Ulm, Germany.
The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently affected genomic regions, the search for candidate genes is ongoing. In parallel, the accurate evaluation of the incidence of chromosome aberrations in CLL by FISH allows the correlation of genetic abnormalities with clinical disease manifestations and outcome. In particular, 17p abnormalities and deletions in 11q22-q23 have already been shown to be among the most important independent prognostic factors identifying subgroups of patients with rapid disease progression and short survival. In addition, deletion 17p has been associated with resistance to treatment with purine analogs. Therefore, genetic abnormalities may allow a risk assessment for individual patients at the time of diagnosis, thus giving the opportunity for a risk-adapted management.
UI - 21379339
AU - Caligaris-Cappio F
TI - Biology of chronic lymphocytic leukemia.
SO - Rev Clin Exp Hematol 2000 Mar;4(1):5-21
AD - Divisione Universitaria di Immunologia Clinica, Ospedale Mauriziano Umberto I, Dipartimento di Scienze Biomediche e Oncologia Umana, Universita di Torino, Torino, Italy.
B-cell chronic lymphocytic leukemia (CLL) lies at the cross-roads of hematology, immunology and oncology for at least three major reasons: (a) it is the prototype of human malignancies that primarily involve defects in the induction of apoptosis; (b) CLL patients develop a severe immunodeficiency with progressive hypogammaglobulinemia; and (c) they have a high prevalence of autoimmune phenomena. Recent advances in the biology of the malignant cell in CLL lead to a scenario comprised of two basic elements: first, CLL cells are optimally organized to survive in their niches because their ability to undergo apoptosis is severely hampered; second, they have a microenvironment-dependence that promotes their extended survival, a situation that arises most probably through direct cell-to-cell contacts. In addition, CLL cells themselves are the major accessory cells in CLL, but are inefficient antigen-presenting cells. This latter defect may provide a clue to reinterpret the events of immunodeficiency and autoimmunity.
UI - 21379342
AU - Orsini E; Guarini A; Foa R
TI - Accessory cells, cytokine loops and cell-to-cell interactions in chronic lymphocytic leukemia.
SO - Rev Clin Exp Hematol 2000 Mar;4(1):73-98
AD - Dipartimento di Biotecnologie Cellulari ed Ematologia, University La Sapienza, Via Benevento 6, 00161 Rome.
In addition to the extensive work that has been conducted in order to understand better the biological features of the leukemic population in B-cell chronic lymphocytic leukemia (CLL), over the years considerable interest has been directed towards other related studies that may have important implications for the accumulation of the leukemic clone and for the immunoparesis typical of this disease. In the present review article, we discuss some of these areas of investigation and, in particular, we focus on: (1) the multiple abnormalities recorded within the T and cytotoxic compartment of patients with CLL; (2) cytokine loops occurring in this disease, with particular emphasis on the cytokines that appear to play a more critical role; and (3) the cell-to-cell cross talk that may be actively operational in CLL. These findings will be discussed in relation with the possible implications that each of them have in the expansion and clinical behavior of a disease that is increasingly proving its heterogeneity.
UI - 21447301
AU - Kaufmann H; Ackermann J; Nosslinger T; Kromer E; Zojer N; Schreiber S;
TI - Urbauer E; Heinz R; Ludwig H; Huber H; Drach J Absence of clonal chromosomal relationship between concomitant B-CLL and multiple myeloma--a report on two cases.
SO - Ann Hematol 2001 Aug;80(8):474-8
AD - University of Vienna, 1st Department of Internal Medicine, Austria.
B-cell chronic lymphocytic leukemia (B-CLL) and multiple myeloma (MM) are chronic B-cell malignancies that represent different stages of B-cell maturation. Occasionally, both diseases are present in the same patient, and this raises the question of clonal associations between the two neoplasms. We here report on two patients with concomitant B-CLL and MM. Clonal chromosomal abnormalities in both lymphocytic cells and plasma cells were studied by interphase fluorescence in situ hybridization (FISH) using a panel of 24 chromosome- and region-specific DNA probes. In the first patient, cytogenetics revealed 47, X, t(Y;22)(p11;q10), +12, dell4(q21q32). By FISH, +12 was present in lymphoid cells, but not in plasma cells. MM cells were characterized by multiple chromosomal gains (1, 11q23) and losses (5q, 10, 13q14, 15, 17p13, Y), which were all undetectable in lymphoid cells. The second patient, in whom no clonal abnormalities were obtained by conventional cytogenetic analysis, had lymphoid cells with loss of 8q24 by FISH. In contrast, evidence for a gain of 8q24 (consistent with amplification of c-myc) was obtained in 13% of plasma cells. Plasma cells were further characterized by gains of chromosomes 1, 3, 11, 18, and Y. We thus conclude that this comprehensive molecular cytogenetic analysis demonstrates the existence of two clonally distinct B-cell malignancies in both patients.
UI - 21455262
AU - Zent CS; Kyasa MJ; Evans R; Schichman SA
TI - Chronic lymphocytic leukemia incidence is substantially higher than estimated from tumor registry data.
SO - Cancer 2001 Sep 1;92(5):1325-30
AD - Division of Hematology/Oncology, Departments of Medicine and Pathology, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. email@example.com
BACKGROUND: Although chronic lymphocytic leukemia (CLL) often is described as the most common leukemia in the U.S. and Western Europe, to the authors' knowledge the true incidence of CLL in the U.S. is unknown. CLL incidence is estimated from tumor registry reports based on tissue pathology and cancer treatment data. Tumor registry data may underestimate the incidence of CLL substantially because CLL can be diagnosed by flow cytometric analysis of peripheral blood cells, and the majority of patients do not require treatment at the time of diagnosis. METHODS: To test the hypothesis that CLL has a higher incidence than estimated from tumor registry data, the authors compared the actual and reported incidence of CLL for a 10-year interval at the Central Arkansas Veterans Healthcare System (CAVHS). The accuracy of surveillance methods for new diagnoses of CLL was confirmed by reviewing the lymphocyte counts in 45,009 CAVHS patients over a 4-year period. RESULTS: The tumor registry correctly reported 58 of 93 patients with CLL (62.4%) who were diagnosed between January 1, 1990 and December 31, 1999. The tumor registry correctly reported 100% of patients with CLL diagnosed between 1990-1991 but reported only 34.5% of patients with CLL diagnosed between 1998-1999. CONCLUSIONS: The incidence of CLL in the CAVHS was 37.6% higher than estimated from tumor registry data due to an increase in the use of peripheral blood immunophenotype as the only diagnostic test for CLL over the time period of the study. These data suggest that the true incidence of CLL may be substantially higher than estimated from tumor registry data. Copyright 2001 American Cancer Society.
UI - 21012800
AU - Basu S; Mitra Basu R
TI - Theophylline as a therapy for chronic lymphocytic leukemia: a case report and review of literature.
SO - Haematologia (Budap) 2000;30(3):225-7
AD - Department of Medical Oncology, Chittaranjan National Cancer Institute, Calcutta, India. firstname.lastname@example.org
We herein, report that theophylline which can induce apoptosis in chronic lymphocytic leukemia (CLL) cells both in vitro and in vivo, also appears to be effective when used clinically to treat an advanced CLL patient.
UI - 21190895
AU - Panasci L; Paiement JP; Christodoulopoulos G; Belenkov A; Malapetsa A;
TI - Aloyz R Chlorambucil drug resistance in chronic lymphocytic leukemia: the emerging role of DNA repair.
SO - Clin Cancer Res 2001 Mar;7(3):454-61
AD - Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada. L.Panasci@hotmail.com
Various mechanisms have been implicated in nitrogen mustard drug resistance. The role of these mechanisms in the development of chlorambucil drug resistance in chronic lymphocytic leukemia (CLL) is discussed. We review these mechanisms with emphasis on the emerging role of DNA repair, and specifically, recombinational repair. Inhibition of these repair processes may lead to new therapies, not only in CLL, but in other malignancies as well.
UI - 21259479
AU - de Vetten MP; van Gelder M; de Greef GE
TI - Recovery of erythropoiesis following allogeneic bone marrow transplantation for chronic lymphocytic leukaemia-associated pure red cell aplasia.
SO - Bone Marrow Transplant 2001 Apr;27(7):771-3
AD - Department of Hematology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, 3008 AE Rotterdam, Netherlands.
Pure red cell aplasia is a rare condition, that can be either idiopathic or associated with a lymphoproliferative disorder. The latter is considered to result from T cell-mediated suppression of haematopoiesis, and usually responds well to treatment with immunosuppressive medication. We describe a patient with B-CLL-associated pure red cell aplasia who did not respond to several courses of immunosuppressive treatment. Erythropoiesis was finally restored after allogeneic bone marrow transplantation.
UI - 21373763
AU - Miller MK; Strauchen JA; Nichols KT; Phelps RG
TI - Concurrent chronic lymphocytic leukemia cutis and acute myelogenous leukemia cutis in a patient with untreated CLL.
SO - Am J Dermatopathol 2001 Aug;23(4):334-40
AD - Departments of Dermatopathology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Patients who have chronic lymphocytic leukemia (CLL) are known to have a high frequency of second malignant neoplasms. However, acute myelogenous leukemia (AML) occurring concurrent with or after a diagnosis of CLL is extremely rare. In this article we report a case of AML developing in a 55-year-old male with a 6-year history of untreated CLL. The diagnosis was facilitated by touch preparation of a skin punch biopsy specimen. The patient presented with a two-week history of fever, weakness, anasarca, and a skin rash. Physical examination revealed pink to skin-colored firm papules, which coalesced into indurated plaques on his trunk, upper extremities, and face. The lesions, in combination with generalized edema, produced a leonine facies. Touch prep of the biopsy showed medium to large blasts, large monocytoid cells, and numerous small mature lymphocytes, providing the preliminary diagnosis of a second, previously undiagnosed myelomonocytic malignancy in this patient. The initial diagnosis was subsequently confirmed by histologic, cytochemical, immunohistochemical and flow cytometry studies. This is the first reported case of CLL with concurrent AML in which rapid touch prep of a skin punch biopsy facilitated diagnosis.
UI - 21426509
AU - Dearden CE; Matutes E; Cazin B; Tjonnfjord GE; Parreira A; Nomdedeu B;
TI - Leoni P; Clark FJ; Radia D; Rassam SM; Roques T; Ketterer N; Brito-Babapulle V; Dyer MJ; Catovsky D High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.
SO - Blood 2001 Sep 15;98(6):1721-6
AD - Royal Marsden NHS Trust, London, United Kingdom. email@example.com
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.
UI - 21426544
AU - Hisada M; Biggar RJ; Greene MH; Fraumeni JF Jr; Travis LB
TI - Solid tumors after chronic lymphocytic leukemia.
SO - Blood 2001 Sep 15;98(6):1979-81
AD - Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20852, USA. firstname.lastname@example.org
Prior reports indicate that patients with chronic lymphocytic leukemia (CLL) may be at increased risk of subsequent neoplasms. This study quantified the risk of second cancers among 16 367 patients with CLL in the population-based Surveillance, Epidemiology and End Results Program. Overall, the observed/expected ratio (O/E) was 1.20 (95% confidence interval [CI], 1.15-1.26). Second cancer risks for patients who received chemotherapy only as the first course of treatment (O/E = 1.21) were similar to risks for those who received no treatment initially (O/E = 1.19). Significant excesses were found for Kaposi sarcoma (O/E = 5.09), malignant melanoma (O/E = 3.18), and cancers of the larynx (O/E = 1.72) and the lung (O/E = 1.66). Increased risks were also found for brain cancer among men (O/E =1.91) and for cancers of the stomach (O/E = 1.76) and bladder (O/E = 1.52) among women. Additional investigations of cancers after CLL are needed to explore the role of immunologic impairment and/or other etiologic influences.
UI - 21449248
AU - Kunzmann V; Ruediger T; Hallek M; Mueller-Hermelink HK; Wilhelm M
TI - Tumor cell agglutination and not solely cytokine release as mechanism of adverse reactions during anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) treatment.
SO - Blood 2001 Sep 15;98(6):1991-2
UI - 21437185
AU - Andersen MK; Christiansen DH; Jensen BA; Ernst P; Hauge G;
TI - Pedersen-Bjergaard J Therapy-related acute lymphoblastic leukaemia with MLL rearrangements following DNA topoisomerase II inhibitors, an increasing problem: report on two new cases and review of the literature since 1992.
SO - Br J Haematol 2001 Sep;114(3):539-43
AD - Cytogenetic Laboratory, Section of Haematology/Oncology, Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark. MKA@rh.dk
A highly increased risk of myelodysplasia (MDS) and acute myeloid leukaemia (AML) is well established in patients previously treated for other malignancies with alkylating agents or topoisomerase II inhibitors. More recently, single cases of acute lymphoblastic leukaemia (ALL), often presenting balanced translocations involving chromosome band 11q23, have been observed. We present two such cases with t(4;11)(q21;q23), one of whom had previously received only single-agent chemotherapy with 4-epi-doxorubicin. A review of the literature since 1992 including these two patients reveals a total of 23 cases of ALL or lymphoblastic lymphoma after chemotherapy presenting balanced translocations to 11q23. All 23 patients had previously received at least one topoisomerase II inhibitor, and in two patients 4-epi-doxorubicin had been administered as single-agent chemotherapy for breast cancer. The latency period to development of t-ALL was 24 months or less in 20 out of 22 cases. The MLL gene was found to be rearranged in 14 out of 14 cases, and in three out of six cases the breakpoint was at the telomeric part of the gene, as observed in most cases of AML following therapy with topoisomerase II inhibitors. These results indicate that patients with ALL and balanced translocations to chromosome band 11q23 following chemotherapy with topoisomerase II inhibitors in the future should be included with cases of MDS or AML in calculations of risk of leukaemia.
UI - 21437194
AU - Wickremasinghe RG; Ganeshaguru K; Jones DT; Lindsay C; Spanswick VJ;
TI - Hartley JA; Wadhwa M; Thorpe R; Hoffbrand AV; Prentice HG; Mehta AB Autologous plasma activates Akt/protein kinase B and enhances basal survival and resistance to DNA damage-induced apoptosis in B-chronic lymphocytic leukaemia cells.
SO - Br J Haematol 2001 Sep;114(3):608-15
AD - Department of Haematology, Royal Free and University College School of Medicine, London, UK. email@example.com
We have studied the actions of autologous plasma on both basal and DNA damage-induced apoptosis in B-chronic lymphocytic leukaemia (B-CLL) cells. Apoptosis was quantified using morphological criteria and Western blot analysis for the apoptosis-specific p85 fragment of poly(ADP ribose) polymerase. Cell viability was estimated using the methyl thiazol tetrazolium bromide dye reduction assay. Plasma cultures showed lower rates of basal apoptosis as well as a decreased cytotoxic response to chlorambucil and gamma-radiation compared with cultures in fetal calf serum. Experiments using neutralizing antibodies suggested that the protective actions of plasma could not be accounted for by interleukin 4, the interferons alpha or gamma or stromal cell-derived factor 1, each of which have been shown to protect B-CLL cells from apoptosis in vitro. Plasma addition to B-CLL cells resulted in rapid activation of the Akt protein kinase, a key signalling enzyme that has been implicated in anti-apoptotic signalling. LY294002, an inhibitor of phosphatidylinositol 3'-kinase, blocked Akt activation by plasma. To the best of our knowledge, this is the first report to show that factors present in plasma promote basal survival of B-CLL cells and resistance to cytotoxic drugs via stimulation of the Akt cytoprotective-signalling pathway. Pharmacological blockade of this pathway may have potential in the development of novel therapeutic strategies for B-CLL treatment.
UI - 21299417
AU - Wolf S; Mertens D; Schaffner C; Korz C; Dohner H; Stilgenbauer S;
TI - Lichter P B-cell neoplasia associated gene with multiple splicing (BCMS): the candidate B-CLL gene on 13q14 comprises more than 560 kb covering all critical regions.
SO - Hum Mol Genet 2001 Jun 1;10(12):1275-85
AD - Abteilung Organisation Komplexer Genome (H0700), Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
Deletions in chromosomal band 13q14.3 occur in >50% of B-cell chronic lymphocytic leukemias (B-CLL) and mantle cell lymphoma, indicating the localization of a tumor suppressor gene involved in the pathomechanism of these diseases. Within a 400 kb recurrently deleted segment at least two minimally deleted subregions had been reported. For the two genes residing in the proximal subregion, initially named LEU1 and LEU2, a pathogenic role has not yet been established. We report here that LEU1 is only a small portion of a large gene, which spans all previously reported critical subregions including the distal subregion. This gene, designated B-cell neoplasia-associated gene with multiple splicing (BCMS), is composed of at least 50 exons spanning >or=560 kb of genomic DNA and is expressed in more than 20 RNA splicing variants. While tissue-specific expression of RNA variants was observed, there was no evidence for the expression of a variant specific for B-CLL. Sequence analysis of the RNA variants suggests that BCMS transcripts belong to the group of non-coding RNAs. The alignment of the gene with all critical subregions provides a strong argument for BCMS being the most likely candidate for the tumor suppressor gene in 13q14 involved in the leukemogenesis of B-CLL. Due to the limited understanding of functional RNAs, however, it remains difficult to prove the pathogenic role of BCMS.
UI - 21469673
AU - Hua XH; Genini D; Gussio R; Tawatao R; Shih H; Kipps TJ; Carson DA;
TI - Leoni LM Biochemical genetic analysis of indanocine resistance in human leukemia.
SO - Cancer Res 2001 Oct 1;61(19):7248-54
AD - Department of Medicine and The Sam and Rose Stein Institute for Research on Aging, University of California, San Diego, La Jolla, California 92093-0663, USA.
Indanocine is a potent tubulin-binding drug that is cytotoxic to multidrug-resistant cancer cell lines. We demonstrated that indanocine specifically induces apoptosis in malignant B cells from patients with chronic lymphocytic leukemia. To address the exact biochemical basis for indanocine toxicity, an indanocine-resistant clone was selected from mutagenized CEM human lymphoblastoid cells. The resistant cells displayed a stable indanocine-resistant phenotype for at least 9 months in drug-free culture. The cloned cells are cross-resistant to colchicine and vinblastine, but not to paclitaxel, and do not have increased expression of the multidrug-resistant p170 glycoprotein. In both parental cells and cell extracts, indanocine treatment caused tubulin depolymerization. In contrast, the tubulin in the resistant clone did not depolymerize under identical conditions. Both extract mixing and cell fusion experiments suggested that a stable structural change in microtubules, rather than a soluble factor, was responsible for indanocine resistance. Sequence analysis of parental and resistant cells revealed a single point mutation in the M40 isotype of beta-tubulin at nucleotide 1050 (G-->T, Lys(350)-->Asn) in the indanocine-resistant clone, in a region close to the putative colchicine binding site.
UI - 21351351
AU - Gharagozloo S; Khoshnoodi J; Shokri F
TI - Hepatitis C virus infection in patients with essential mixed cryoglobulinemia, multiple myeloma and chronic lymphocytic leukemia.
SO - Pathol Oncol Res 2001;7(2):135-9
AD - School of Public Health, Tehran University of Medical Sciences, Department of Immunology, Tehran 14155, I.R. Iran.
Increased prevalence of HCV infection in some lymphoproliferative diseases has been recently reported. In the present study, the frequency of anti-HCV antibody (Ab) together with hepatitis B surface (HBs) antigen (Ag) and anti-HBs Ab were determined in 42, 45 and 23 patients with essential mixed cryoglobulinemia (EMC), multiple myeloma (MM) and B-cell chronic lymphocytic leukemia (B-CLL), respectively. Thirty hospitalized patients with chronic rheumatoid arthritis (RA) were also included as a control. Specific antibodies to HCV antigens were detected by enzyme linked immunosorbent assay (ELISA) and positive results were confirmed by a recombinant immunoblot assay (RIBA). Our results demonstrated anti-HCV positivity in 69%, 11% and 4.3% of the EMC, MM and B-CLL samples tested, respectively. None of the RA patients were found to be anti-HCV positive. No significant differences were observed between the patients groups regarding the frequency of HBs Ag and anti-HBs Ab. Considering the low incidence of HCV infection in the control group and the normal population, these results confirm and extend previous reports on the possible role of HCV infection in the etiology of EMC and further suggest involvement of this virus in a subset of MM.
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