Shinsuke Kataoka

Recurrent MYB rearrangement in blastic plasmacytoid dendritic cell neoplasm

Lymphoproliferative Disorders Team, Centre de Recherche des Cordeliers, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Service d’Hématologie Biologique, GH Pitié-Salpêtrière, Paris, France; Service de Biostatistique et Informatique Médicale, Hôpital Saint Louis, Paris, France.; Département de génétique, GH Pitié-Salpêtrière, Paris, France; INSERM U1170, Institut Gustave Roussy, Villejuif, France; Département d’Hématologie, Hôpital Becquerel, Rouen, France; Pôle d’Hématologie, Hôpital Brabois, Vandoeuvre-les-Nancy, France; Service d’Hématologie Clinique, Hôpital d’Argenteuil, Argenteuil, France and Karyopharm Therapeutics, Newton, MA, USA E-mail: santos.susin@crc.jussieu.fr or florence.nguyen-khac@psl.aphp.fr These authors contributed equally to this work. Senior coauthorship.

Development of clinical paroxysmal nocturnal haemoglobinuria in children with aplastic anaemia

The clinical significance of paroxysmal nocturnal haemoglobinuria (PNH) in children with aplastic anaemia (AA) remains unclear. We retrospectively studied 57 children with AA between 1992 and 2010. During the follow‐up, five patients developed clinical PNH, in whom somatic PIGA mutations were detected by targeted sequencing. The 10‐year probability of clinical PNH development was 10·2% (95% confidence interval, 3·6–20·7%). Furthermore, the detection of minor PNH clones by flow cytometry at AA diagnosis was a risk factor for the subsequent development of clinical PNH. These patients with PNH clones at AA diagnosis should undergo periodic monitoring for potential clinical PNH development.

Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR

Insertional mutagenesis is an important risk with all genetically modified cell therapies, including chimeric antigen receptor (CAR)-T cell therapy used for hematological malignancies. Here we describe a new tagmentation-assisted PCR (tag-PCR) system that can determine the integration sites of transgenes without using restriction enzyme digestion (which can potentially bias the detection) and allows library preparation in fewer steps than with other methods. Using this system, we compared the integration sites of CD19-specific CAR genes in final T cell products generated by retrovirus-based and lentivirus-based gene transfer and by the piggyBac transposon system. The piggyBac system demonstrated lower preference than the retroviral system for integration near transcriptional start sites and CpG islands and higher preference than the lentiviral system for integration into genomic safe harbors. Integration into or near proto-oncogenes was similar in all three systems. Tag-PCR mapping is a useful technique for assessing the risk of insertional mutagenesis.

A patient with a GNAO1 mutation with decreased spontaneous movements, hypotonia, and dystonic features

We report on a 4-year-old girl with a de novo GNAO1 mutation who had neurological findings, including decreased spontaneous movements, hypotonia, and dystonic features. She was referred to our hospital because of delayed psychomotor development. She showed hypotonia and decreased spontaneous movements. Voluntary movements of the limbs were more frequent in the lower extremities than in the upper extremities. Occasional dyskinetic features, such as awkward hand/foot posturing and grimacing, were seen during the voluntary movements. Serum metabolic screening, head magnetic resonance imaging, and electroencephalography were unremarkable. Whole-exome sequencing revealed a de novo mutation in the patients GNAO1 gene, c.709 G > A (p.E237K). We calculated the free-energy change using the FoldX Suite to evaluate the impact of the E237K mutation. The FoldX calculations showed an increased free-energy change in the active state of the GNAO1 protein, indicating that the E237K mutation destabilizes the active state complexes. No seizures, chorea, tremor, or myoclonia, which are frequently reported in patients with GNAO1 mutations, were observed as of the last follow up. Our patient will improve the understanding of early neurological features in patients with GNAO1 mutations.

A case of lamellar ichthyosis due to a novel TGM1 mutation associated with Parkinson's disease

The transglutaminase 1 (TGM1) gene is a major causative gene of autosomal recessive congenital ichthyoses (ARCI), including lamellar ichthyosis (LI), congenital ichthyosiform erythroderma, self-healing/self-improving collodion baby, and bathing suit ichthyosis (BSI) [1, 2]. Additionally, a mutation in the epidermal lipase N gene (LIPN) was found to cause a late-onset form of ARCI [3]. To date, 12 genes responsible for ARCI have been identified: TGM1, ALOX12B, ALOXE3, ABCA12, CYP4F22, NIPAL4, SDR9C7, [...]