Abstract:
:Multiple Myeloma (MM) is a haematological malignancy characterised by the clonal expansion of plasma cells (PCs) within the bone marrow. Despite advances in therapy, MM remains a largely incurable disease with a median survival of 6 years. In almost all cases, the development of MM is preceded by the benign PC condition Monoclonal Gammopathy of Undetermined Significance (MGUS). Recent studies show that the transformation of MGUS to MM is associated with complex genetic changes. Understanding how these changes contribute to evolution will present targets for clinical intervention. We discuss three models of MM evolution; the linear, the expansionist and the intraclonal heterogeneity models. Of particular interest is the intraclonal heterogeneity model. Here, distinct populations of MM PCs carry differing combinations of genetic mutations. Acquisition of additional mutations can contribute to subclonal lineages where "driver" mutations may influence selective pressure and dominance, and "passenger" mutations are neutral in their effects. Furthermore, studies show that clinical intervention introduces additional selective pressure on tumour cells and can influence subclone survival, leading to therapy resistance. This review discusses how Next Generation Sequencing approaches are revealing critical insights into the genetics of MM development, disease progression and treatment. MM disease progression will illuminate possible mechanisms underlying the tumour.
journal_name
Br J Haematoljournal_title
British journal of haematologyauthors
Dutta AK,Hewett DR,Fink JL,Grady JP,Zannettino ACWdoi
10.1111/bjh.14649subject
Has Abstractpub_date
2017-07-01 00:00:00pages
196-208issue
2eissn
0007-1048issn
1365-2141journal_volume
178pub_type
杂志文章,评审abstract::Interleukin-6 (IL6) plays a central role in multiple myeloma pathogenesis and confers resistance to corticosteroid-induced apoptosis. We therefore evaluated the efficacy and safety of siltuximab, an anti-IL6 monoclonal antibody, alone and in combination with dexamethasone, for patients with relapsed or refractory mult...
journal_title:British journal of haematology
pub_type: 杂志文章,多中心研究
doi:10.1111/bjh.12266
更新日期:2013-05-01 00:00:00
abstract::Comparative genomic hybridization (CGH) was used to analyse 34 follicular lymphoma (FL) samples. 27 samples showed DNA sequence copy number changes of at least one genomic region (26 samples with at least one gain and nine with at least one loss). Some chromosomes or chromosomal regions were preferentially involved. T...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.d01-2140.x
更新日期:1997-04-01 00:00:00
abstract::We report the clinical outcome and results of chimaerism analysis in various cell lineages of 30 patients given non-myeloablative conditioning, followed by allogeneic stem cell transplantation (SCT). The commonest diagnoses were chronic myelogenous leukaemia (n = 11) and solid tumours (n = 11). Twenty-one patients rec...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2001.03174.x
更新日期:2001-12-01 00:00:00
abstract::Mantle cell lymphoma (MCL) is an incurable mature B cell proliferation, combining the unfavourable clinical features of aggressive and indolent lymphomas. The blastic variant of MCL has an even worse prognosis and new treatment options are clearly needed. We analysed the effects of BL22, an immunotoxin composed of the...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2009.07939.x
更新日期:2010-01-01 00:00:00
abstract::In myeloid malignancies, T-cell and NK function has been shown to deteriorate with transformation from pre-leukaemia to advanced disease. Immune dysfunction in solid tumours has been attributed to abnormal signal transduction, possibly through altered expression of intracellular components of the TCR/CD3 complex (e.g....
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.00654.x
更新日期:1998-03-01 00:00:00
abstract::Nine patients with Fanconi anaemia (FA) were conditioned for HLA-identical sibling bone marrow transplant (BMT) with reduced dose of cyclophosphamide (Cy) without radiation or antithymocyte globulin (ATG). The total dose of Cy was 140 mg/kg (n = 2) or 120 mg/kg (n = 7). The median patient age was 8 years (range 4-19)....
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1996.363898.x
更新日期:1996-03-01 00:00:00
abstract::Dyskeratosis congenita (DC) is an inherited disorder characterized by skin pigmentation, nail dystrophy and mucosal leucoplakia. In 1995 a Dyskeratosis Congenita Registry was established at the Hammersmith Hospital. In the 46 families recruited, 76/83 patients were male, suggesting that the major form of DC is X-linke...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1998.01103.x
更新日期:1998-12-01 00:00:00
abstract::Tumour necrosis factor-α (TNF) is an inflammatory cytokine that is elevated in a number of autoimmune diseases including immune thrombocytopenia (ITP), a bleeding disorder characterized by low platelet counts. In vitro TNF blockade increases expansion of the regulatory T cell (Treg) IKZF2 (also termed Helios) subset i...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/bjh.13126
更新日期:2015-01-01 00:00:00
abstract::Allogeneic sibling bone marrow transplantation (BMT) is the recommended treatment for relapsed childhood acute lymphoblastic leukaemia (ALL), but appropriate donors are only available in 30% of cases. Unfortunately, BMT from unrelated donors (UD) has been associated with high rates of severe graft-versus-host disease ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1996.d01-1834.x
更新日期:1996-09-01 00:00:00
abstract::The addition of rituximab (R) to CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy was a milestone in the development of front-line therapy for diffuse large B-cell lymphoma (DLBCL). R-CHOP and equivalent rituximab-containing anthracycline-based regimens are now widely accepted as the standard...
journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/j.1365-2141.2008.07383.x
更新日期:2008-12-01 00:00:00
abstract::A mutation in factor XIII (Val34Leu) was reported to protect against venous thromboembolism. We evaluated the effect of Val34Leu on thrombotic risk in 352 factor V Leiden carriers who were first-degree relatives of 132 thrombotic propositi carrying factor V Leiden. The total observation period was 2,594 years in 92 Va...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.02338.x
更新日期:2000-10-01 00:00:00
abstract::The specific sodium pump antagonist ouabain was used to study the effect of sodium pump inhibition on granulopoietic colony formation by normal human bone marrow cells cultured in soft agar for 7 d. Suppression of colony formation was dose-dependent and occurred at a low and reproducible concentration. The use of an e...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1982.tb02795.x
更新日期:1982-07-01 00:00:00
abstract::Platelets from patients with platelet-type von Willebrand disease (vWD) were used as immunogens for the production of murine monoclonal antibodies (MoAbs). One such MoAb, C-34, inhibited ristocetin-induced aggregation of patient or normal platelets, but not aggregation induced by other aggregating agents. As demonstra...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1990.tb02589.x
更新日期:1990-03-01 00:00:00
abstract::Primary mediastinal B-cell lymphoma (PMBL) shows chromosome 9p anomalies in 50% of cases. Based on reports that p16INK4A gene, located on this chromosomal arm, is frequently altered in aggressive lymphomas, we analysed for alterations of this gene in 27 cases of PMBL, which were part of a series of 32 PMBL cases that ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1999.01678.x
更新日期:1999-10-01 00:00:00
abstract::In type 1 Gaucher disease a bleeding tendency occurs which is partly caused by thrombocytopenia due to massive splenomegaly. In addition, low levels of factors IX and XI have been described. The mechanism responsible for these clotting factor abnormalities is unknown. We performed a detailed study of parameters of coa...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.1997.d01-2076.x
更新日期:1997-03-01 00:00:00
abstract::A patient with familial analpha-lipoproteinaemia (Tangier disease) was found to have stomatocytosis and haemolytic anaemia. The analysis of the red cell membrane constituents revealed a low cholesterol content (90 nmol/ml red cells, control 130 nmol/ml red cells), a decreased cholesterol/phospholipid ratio (0.54, cont...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1989.tb07694.x
更新日期:1989-06-01 00:00:00
abstract::In this population-based survey covering two geographically distinct UK regions, we evaluated the number of myeloma patients aged < or =65 years who have not undergone transplantation. The combined data from both of these regions showed that 57% of age-eligible patients were not transplanted. While early death and com...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2004.05340.x
更新日期:2005-02-01 00:00:00
abstract::Of 125 patients aged 65 years or over, with atrial fibrillation taking warfarin for at least 12 months, with a standard deviation (SD) of prothrombin time, expressed as the International Normalized Ratio (INR) >0.5 over the previous 6 months, 40 were randomized to continue with usual clinic care and 85 to receive educ...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2141.2004.05074.x
更新日期:2004-08-01 00:00:00
abstract::A case of Evans' syndrome with IgM deficiency and lymphopenia was studied before and after splenectomy. The lymphopenia was as a result of profound reduction of CD4 and CD8 cells. Study of cytokine secretion before splenectomy revealed a spontaneous Th1- and Th2-type cytokine production, and complete suppression of tr...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.02296.x
更新日期:2000-09-01 00:00:00
abstract::Thrombocytopenia is typically observed in patients undergoing cord blood transplantation. We hypothesized that delayed recovery of the platelet count might be caused by defects in the megakaryocytic differentiation pathway of cord blood progenitors. To test this hypothesis, we compared the features of in vitro megakar...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.01854.x
更新日期:2000-03-01 00:00:00
abstract::We present the results of a novel method developed for evaluation of in situ amplification, a molecular genetic method at the cellular level. Reverse transcription polymerase chain reaction (RT-PCR) was used to study bcr-abl transcript levels in individual cells from patients with chronic myelogenous leukaemia (CML). ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2001.02510.x
更新日期:2001-03-01 00:00:00
abstract::We have characterized the molecular defect in two families with severe factor VII (FVII) deficiency. In family I, the proband was found to be homozygous for a novel 18 bp deletion in exon 8 (g.10896-10913del) resulting in the in-frame deletion of six amino acids in the serine protease domain. Molecular modelling sugge...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.2004.04997.x
更新日期:2004-07-01 00:00:00
abstract::Splanchnic vein thrombosis (SVT) is one of the most important complications of myeloproliferative neoplasms (MPN). Although MPN are common causes of SVT, the pathophysiological mechanisms underlying this predisposition, their epidemiology and natural history are not fully understood. Studies have concentrated on the g...
journal_title:British journal of haematology
pub_type: 杂志文章,评审
doi:10.1111/bjh.12461
更新日期:2013-09-01 00:00:00
abstract::We report a high incidence of subacute, chronic and sometimes occult intracranial subdural haematoma (SDH) occurring during intensive chemotherapy for acute myeloid leukaemia (AML) with a monoblastic component. Between March 1990 and January 1993, 86 AML patients from our institution were randomized in the multicentri...
journal_title:British journal of haematology
pub_type: 临床试验,杂志文章,随机对照试验
doi:10.1111/j.1365-2141.1995.tb08358.x
更新日期:1995-03-01 00:00:00
abstract::Non-endemic Burkitt lymphoma (BL) is a rare germinal centre B-cell-derived malignancy with the genetic hallmark of MYC gene translocation and with rapid tumour growth as a distinct clinical feature. To investigate treatment outcomes, loss of lifetime and relapse risk in adult BL patients treated with intensive immunoc...
journal_title:British journal of haematology
pub_type: 杂志文章,多中心研究
doi:10.1111/bjh.16425
更新日期:2020-05-01 00:00:00
abstract::Bone marrow (BM) from patients affected by multiple myeloma (MM), exhibiting monoclonal gammopathy of undetermined significance (MGUS) or with non-Hodgkin lymphoma (NHL) as well as from healthy donors were investigated for the presence of human herpesvirus-8 (HHV-8) DNA sequences. ORF 26 sequences were detected in 36-...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2001.02702.x
更新日期:2001-04-01 00:00:00
abstract::This communication reports a patient with concomitant expansions of CD4+ and CD8+ large granular lymphocytes. Immunological analyses revealed that the abnormally increased CD4+ LGL fraction was phenotypically similar to other reported persistent CD4+ LGL expansions, whereas the phenotypic profile for the CD8+ LGL comp...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1994.tb05087.x
更新日期:1994-11-01 00:00:00
abstract::Factor V Leiden (FVL)-carrying relatives of selected patients with venous thromboembolism (VTE) have much higher venous thrombotic risks than FVL-carrying relatives of unselected consecutive patients with VTE. To find an explanation for this, we explored other risk factors of VTE, in particular the presence of high fa...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2001.02946.x
更新日期:2001-08-01 00:00:00
abstract::Purpura fulminans (PF) is a cutaneous manifestation of a dramatic and deadly syndrome of systemic disseminated intravascular coagulation (DIC). It is characterized by microvascular thrombosis in the dermis followed by perivascular haemorrhage. Since two other related syndromes involve the protein C (PC) system, we und...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1111/j.1365-2141.1990.tb02625.x
更新日期:1990-05-01 00:00:00
abstract::Inhibitor formation in patients with haemophilia receiving factor VIII (FVIII) concentrate is a common problem requiring tolerance induction therapy. Immune tolerance is dependent on defective T cell/antigen-presenting cell (APC) interactions and inhibitor antibody formation is associated with effective T-cell/B-cell ...
journal_title:British journal of haematology
pub_type: 杂志文章
doi:10.1046/j.1365-2141.2000.01994.x
更新日期:2000-04-01 00:00:00