50th Annual Scientific Meeting of the British Society for Haematology

Abstract

The 50th Annual Scientific Meeting of the British Society for Haematology was notable, not only for its golden anniversary, but also because it coincided with the eruption of the Icelandic volcano, Eyjafjallajökull, and the ensuing travel chaos. In total, 28 speakers from overseas were unable to reach Edinburgh, including a significant number of British speakers who were stranded. However, owing to the superb efforts of the conference organisers and Edinburgh International Conference Centre staff, teleconferencing equipment was installed and all speakers were contacted and able to give their talks on time. The program, consisting of simultaneous sessions and plenary lectures, covered not only recent advances in clinical and laboratory hematology, but also reflected on the contribution of British hematology to the international arena over the past 50 years.

Monday 19th April

The pediatric symposium was one of four simultaneous sessions that opened the meeting. Kjeld Schmiegelow from the University of Copenhagen (Denmark) discussed ‘Pediatric acute lymphoblastic leukemia: the cost of cure’. Studies of survivors of children’s cancer show that 62% have chronic health conditions [1]. With increasing intensity of treatment and better supportive care, the cure rate has risen from 20% in the 1960s to more than 80% today. However, of children with acute lymphoblastic leukemia (ALL), 50% could be cured by less-intensive therapy and 25% will relapse, despite intensification of therapy. Identifying ways to individualize treatment may lead to a better balance between toxicity and cure. Techniques such as detection of minimal residual disease have been employed to modify treatment, and also pharmacogenomics could be used to optimize individual dosing of chemotherapeutic drugs. Metabolism of methotrexate was used as an example of how genetic variation can modify a patient’s handling of drugs. SLC19A1 encodes for a folate transporter protein, which also actively transports methotrexate into cells. A polymorphism (c.80AA) results in increased cellular methotrexate influx, which may improve efficacy. SLC19A1 is found on chromosome 21 and the polymorphism appears to interact with copy number, influencing methotrexate efficacy and toxicity [2]. Personalized dosing may exploit these findings. The positive message is that most survivors of cancer can live normal lives but, by using genetic profiling on patients and tumor, cure rate and toxicity can be optimized by truly tailoring therapy to the individual. Local and national life-long follow-up studies of these children are essential.

Mitchell Weiss from the Children’s Hospital of Philadelphia (PA, USA) gave the second talk, where he discussed ‘Chaperone proteins and erythropoiesis’. During maturation of the erythrocyte, there is accumulation of hemoglobin, nuclear condensation, decrease in cell size and loss of organelles. Chaperone proteins mediate all these functions. The concentration of hemoglobin in red blood cells is 350 g/l, resulting in intense crowding, which may interfere with protein folding and, ultimately, maturation. The component parts of hemoglobin are labile and toxic individually, and must be balanced. In the thalassemias, there is chain imbalance, and heme and oxygen stress. Molecular chaperones fold normal proteins, promote refolding of misfolded or damaged proteins and remove irreversibly damaged proteins. They also bind to native protein to modulate function. The α-hemoglobin-stabilizing protein (AHSP) is specific to the red blood cell, and prevents α-hemoglobin aggregation by folding it into a stable form. Can AHSP modulate pathological states of α-hemoglobin excess, such as in β-thalassemia? In mice, it appears it does, but in humans, it is not certain and it probably plays only a minor role [3]. Toxic aggregated proteins are also compartmentalized into aggresomes that use the ubiquitin–proteosome system (UPS) and chaperone proteins to regulate protein degradation. Where protein aggregation exceeds the capacity of the chaperone proteins, diseases may occur, and this is seen in β-thalassemia major. Those with β-thalassemia trait are normal, as the erythroblasts can both bind and degrade the excess α-hemoglobin using AHSP and the aggresomes. However, these mechanisms are overwhelmed in β-thalassemia and the free toxic α-hemoglobin also inhibits normal quality-control function.

The session concluded with Tony Segal of the University College London (UK) speaking on ‘Congenital disorders of the neutrophil respiratory burst’. Segal described how the failure of the respiratory burst in chronic granulomatous disease (CGD) results in increased infection, but pointed out the anomaly that although some patients with CGD have up to 30% respiratory burst, there is grossly abnormal function of the neutrophils. In knockout mouse models, if neutral proteases in neutrophil granules, such as elastase and cathepsin G, were not present, organisms were not killed, despite making superoxides [4]. The membrane-bound enzyme NADPH oxidase, which has decreased activity in CGD, pumps electrons into the phagocytic vacuole. To compensate, K⁺ passes into the vacuole and the pH within the vacuole rises and then slowly drops; in CGD, the pH falls. This process results in H⁺ ions, and superoxides are formed. The pH change and ion fluxes are important as they activate the granule proteins and produce conditions conducive to microbial killing and digestion by enzymes released from the cytoplasmic granules [5].

Pier Mannucci from the Hospital Foundation and University of Milan (Italy) gave the British Society for Haemostasis and Thrombosis (BSHT) MacFarlane Biggs Plenary Lecture, entitled ‘Hemophilia and related bleeding disorders: the next 10 years’; he also reflected on hemophilia treatment over the past 50 years. He described the progress made in treatment, from the cryoprecipitate of the 1960s to the recombinant products of today, with gene therapy still a tantalizing goal. He outlined possible developments in therapy, including production of long-acting recombinant products by chemical or genetic modification, coagulation factors from milk of transgenic pigs, and natural inhibitors of coagulation, such as anti-tissue factor pathway inhibitor or anti-antigen-presenting cell agents. Mannucci then focused on the management difficulties of age-related complications facing elderly patients with hemophilia, such as cardiovascular disease, cancer and prostatic hypertrophy. In Italy, the life expectancy of a patient with hemophilia is near that of the general population. However, Mannucci also highlighted that there was no treatment for at least two-thirds of those with hemophilia in the world.

Tuesday 20th April

James Downing of St Jude’s Children’s Research Hospital (USA) delivered the British Journal of Haematology (BJH) Trust and Wilkinson Memorial lecture on ‘Genetics of acute lymphoblastic leukemia’. He explained that identified chromosomal translocations are only single targets and that a ‘complement of lesions’ is needed for leukemia to develop. Examples of altered pathways in leukemia development are the BCR–ABL translocation altering response to growth signals, and AML1-ETO allowing self-renewal. Alone, these do not generate leukemia; a block in the apoptotic pathway is also needed. In his laboratory, the total complement of abnormalities, including copy number of genes, in an individual’s malignancy is identified [6]. Molecular profiling, including chromosomal analysis, whole-gene and expression array analysis, can be used to select genes for targeting and sequencing. He focused on the transcription factors Ikaros and PAX 5. Deletions or amplifications of PAX5 are found in 30% of cases of B-cell ALL, and can lead to different fusion proteins or partner genes that play a direct role in differentiation. In BCR–ABL-positive ALL, a deletion of PAX 5 is found in 50% of patients. Ikaros is a transcription factor that binds the DNA, resulting in dimerization. Full disruption of this binding can lead to a block in differentiation, whereas partial disruption can lead to proliferation. Ikaros is deleted in 83.7% of BCR–ABL-positive ALL [7]. Patients with TEL–AML-positive leukemias may be BCR–ABL positive, but they never have an Ikaros deletion. Interestingly, in chronic myeloid leukemia, a deletion of Ikaros is never seen in the chronic phase, but appears in blast crisis [7]. The mouse model shows cooperation of the Ikaros deletion and expression of BCR–ABL in generation of ALL. Molecular array analysis was studied in cells from high-risk pediatric ALL cases, excluding those with genetic risk factors known to be associated with high risk (e.g., BCR–ABL positive). An Ikaros deletion alone was found to be associated with a 75% chance of relapse and that those with no deletion had a 25% chance of relapse. Downing and his team plan to perform whole-genomic sequencing of 600 tumor and normal pairs, focusing on high-risk tumors in each tumor subtype.

One afternoon session comprised presentations of clinical vignettes. These included a case of copper deficiency causing reversible myelodysplastic syndrome secondary to zinc poisoning from swallowing denture adhesive.

Wednesday 21st April

Doug Higgs from the John Radcliffe Hospital in Oxford (UK) gave the final talk, the British Society for Haematology (BSH) Medal Lecture on ‘Regulation of a globin genes’. Higgs explained that in β-thalassemia major, reducing excess α-globin chains can modify the disease. This occurs with reactivation of γ-chain synthesis or coinheritance of α-thalassemia. To improve the β-thalassemia phenotype, therefore, the goal is to downregulate α-globin gene expression. The regulatory elements of the α-gene cluster include seven highly conserved tyrosine kinase binding sites that are packaged into chromatin. Subpopulations of differentiating erythroblasts were purified and the chromatin immunoprecipitated to see which tyrosine kinases were bound and where chromatin modification was occurring [8]. Early erythroblasts show four binding sites upstream of the regulatory elements, whereas later erythroblasts show promoter binding at three sites. Can mutations in transacting factors cause α-thalassemia, and could this be used therapeutically? Higgs compared two disorders: α-thalassemia with mental retardation (ATRX) syndrome, and acquired α-thalassemia myelodysplastic syndrome. In both conditions, regulatory elements and globin genes are normal. However, mutations in the ATRX gene encode for proteins that bind to and downregulate the α-gene. Diverse changes in the pattern of DNA methylation occur, which may provide a link between chromatin remodeling, DNA methylation and gene expression in developmental processes. In acquired α-thalassemia myelodysplastic syndromeS, the mutation is the same, but is associated with much more severe α-thalassemia; currently, the team is looking for a second mutation. The ATRX pathway regulating α-gene expression is newly characterized, and may lead to exciting new therapeutic developments [9].

The morphology session, as always, rounded up the conference. First, there was a quiz for the assembled audience, older members needing to sit near the front to appreciate the slides showing minute parasites not otherwise visible and, second, the alarmingly exposing practice of individuals giving their expert opinion on complex and difficult blood films with minimal help from their friends.

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.