Oliver Tunstall

Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21

The 40-fold increase in childhood megakaryocyte-erythroid and B-cell leukemia in Down syndrome implicates trisomy 21 (T21) in perturbing fetal hematopoiesis. Here, we show that compared with primary disomic controls, primary T21 fetal liver (FL) hematopoietic stem cells (HSC) and megakaryocyte-erythroid progenitors are markedly increased, whereas granulocyte-macrophage progenitors are reduced. Commensurately, HSC and megakaryocyte-erythroid progenitors show higher clonogenicity, with increased megakaryocyte, megakaryocyte-erythroid, and replatable blast colonies. Biased megakaryocyte-erythroid–primed gene expression was detected as early as the HSC compartment. In lymphopoiesis, T21 FL lymphoid-primed multipotential progenitors and early lymphoid progenitor numbers are maintained, but there was a 10-fold reduction in committed PreproB-lymphoid progenitors and the functional B-cell potential of HSC and early lymphoid progenitor is severely impaired, in tandem with reduced early lymphoid gene expression. The same pattern was seen in all T21 FL samples and no samples had GATA1 mutations. Therefore, T21 itself causes multiple distinct defects in FL myelo- and lymphopoiesis.

EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications

The EBF1-PDGFRB gene fusion accounts for <1% of B-cell precursor acute lymphoblastic leukemia (ALL) cases and occurs within the Philadelphia-like ALL subtype. We report 15 EBF1-PDGFRB-positive patients from childhood ALL treatment trials (ALL 97/99, UKALL 2003, UKALL 2011) in the United Kingdom. The fusion arose from interstitial deletion of 5q33 (n = 11), balanced rearrangement (n = 2), or complex rearrangement (n = 2). There was a predominance of females (n = 11), median age of 12 years, and median white blood cell count of 48.8 × 10(9)/L. Among 12 patients who achieved complete remission on earlier trials (ALL 97/99 and UKALL 2003), 10 were positive for minimal residual disease (MRD) at the end of induction, and 7 relapsed 18 to 59 months after diagnosis. The majority (9 of 12) remained alive 6 to 9 years after diagnosis. There are reports of EBF1-PDGFRB-positive patients who are refractory to conventional chemotherapy who achieve complete response when treated with the tyrosine kinase inhibitor imatinib. These findings have prompted screening for EBF1-PDGFRB in patients entered onto the current UKALL 2011 trial for whom induction therapy failed, who did not achieve remission by day 29, or who remained MRD positive (>0.5%) at week 14. Two UKALL 2011 patients, positive for EBF1-PDGFRB, received imatinib; 1 died 6 months after a matched unrelated bone marrow transplant as a result of undefined encephalopathy, and the other remained in remission 10 months after diagnosis.

Role of GATA-1s in early hematopoiesis and differences between alternative splicing in human and murine GATA-1.

To the editor: We read with interest the description by Hoeller et al of an exon 2 GATA-1 mutation leading to severe transient myeloproliferative disease (TMD),[1][1] in which the authors speculated that the severe phenotype might reflect loss of both full-length (FL) GATA-1 and the shorter isoform

Strategies for reducing inhibitor formation in severe haemophilia.

The greatest barrier to successful haemophilia A care in resource‐rich countries is the development of inhibitors to therapeutic factor VIII. Children with inhibitors suffer through increased bleeding and joint damage as well as frequent venepuncture. Costs associated with inhibitors are beyond many healthcare systems. Over the last two decades, there has been no improvement in our ability to reduce inhibitor development. Current strategies based on early prophylaxis and avoidance of immunological danger signals have given rise to conflicting results. Registry data suggest an increasing problem. Our understanding of the immunological systems involved in inhibitor formation should inform efforts to prevent inhibitors. Great efforts with mouse models are being undertaken in this field. However, there is no guarantee of the availability of any new agents arising from experimental work in the near future. Global immunomodulatory agents may be one solution. Compounds with a long history of use in inflammatory conditions have demonstrated efficacy in preventing antibodies to protein therapeutics both in animal models and in humans. As these compounds have a long history of use in humans, including babies, it may be that these agents offer an option for reducing inhibitor formation in previously untreated patients.

Guidelines for the investigation and management of Transient Leukaemia of Down Syndrome.

Oliver Tunstall, Writing Group Chair, Neha Bhatnagar, Beki James, Alice Norton, Aengus S. O’Marcaigh, Tim Watts, Anne Greenough, Paresh Vyas, Irene Roberts and Michael Wright (BSH Guidelines Task Force Member), On behalf of the British Society for Haematology Bristol Royal Hospital for Children, University Hospitals Bristol NHS Trust, Bristol, John Radcliffe Hospital, Oxford University Hospitals NHS Trust and Oxford BRC Blood Theme, NIHR Oxford Biomedical Centre, Oxford, Leeds Children’s Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, Birmingham Children’s Hospital NHS Trust, Birmingham, UK, Our Lady’s Children’s Hospital, Crumlin, Dublin, Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Trust, King’s College, London, MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Paediatrics, Oxford University, Oxford, and West Hertfordshire Hospitals NHS Trust, Watford, UK

Evaluation of coagulopathy before and during induction chemotherapy for acute lymphoblastic leukaemia, including assessment of global clotting tests

Evaluation of coagulopathy before and during induction chemotherapy for acute lymphoblastic leukaemia, including assessment of global clotting tests

Subclavian vein thrombosis in an otherwise healthy 9-year-old boy

We report a previously well 9-year-old boy who presented with an acutely swollen left arm after horse riding. Left subclavian vein thrombosis was demonstrated by MR venography but there was no evidence of an underlying anatomical abnormality. The child was successfully treated with catheter directed thrombolysis and anticoagulation with intravenous unfractionated heparin and warfarin. We have identified 75 previously published case reports of effort-induced upper extremity deep vein thrombosis (UEDVT) and surveyed patient characteristics and precipitating activities. In this case and literature review, we demonstrate that individuals with effort-induced UEDVT show demographic characteristics and presenting features that are distinct from other patient groups with venous thromboembolic disease. We also highlight the difficulties in counselling affected individuals about modifying occupational and recreational activities to minimise the risk of recurrent thrombosis.

CAPS: a rare acute abdomen

An 11-year-old girl presented to the hospital with vomiting, left upper-quadrant pain and blood in the stool. An ultrasound scan showed no blood flow in the coeliac axis or the splenic artery. A contrast-enhanced CT scan then demonstrated no flow beyond the coeliac axis origin, a large clot in the distal superior mesenteric artery (SMA), a large splenic infarct and bilateral renal infarcts. Investigations revealed a positive lupus anticoagulant and she was given a presumptive diagnosis of catastrophic antiphospholipid syndrome (CAPS). She was anticoagulated and started on combination immunosuppressive therapy. Her surgical management was by SMA embolectomy, small bowel resection and proximal stoma formation. Stoma closure was performed at 3 months, and she was eventually established on full enteral feeds. Childhood CAPS is a rare condition with a very high mortality rate, and the successful outcome in this case reflects close multidisciplinary teamwork between medical and surgical specialties.