Clonal evolution in children with inherited bone marrow failure syndromes

Title : Clonal evolution in children with inherited bone marrow failure syndromes

Abstract:

Inherited bone marrow failure syndromes (IBMFS) are a heterogeneous group of disorders with ineffective haematopoiesis due to underlying germline genetic defects and increased risk of developing of myeloid malignancies. Germline defects impair the fitness of hematopoietic stem cells (HSCs), so HSCs try to improve their fitness by acquiring additional somatic variants. The aim of our study is to evaluate the spectrum of somatic mutations in children with IBFMS, who underwent a comprehensive laboratory examination and treatment in Dmitry Rogachev National Research Centre. To assess the clonal evolution we performed the high-throughput sequencing (NGS) using a customized amplification-based panel of genes (Parseq Lab, Russia). Somatic status of identified variants was confirmed in buccal epithelium when available. The IBFMS in our study were represented with Shwachman-Diamond syndrome (SDS), severe congenital neutropenia (SCN), Diamond-Blackfan anemia (DBA), SAMD9/SAMD9L-associated syndromes, RUNX1-familial platelet disorder, GATA2-deficiency, Fanconi anemia (FA), RAD50-deficiency and DDX41-associated susceptibility to MN. Our data demonstrated several mechanisms for improving HSC fitness, including somatic compensation and events that could lead to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in different patient groups. The largest cohort of patients with previously established SDS showed various types of clonal events, including a new variant in the SBDS gene that was not previously described; some of them were with additional structural chromosome alterations. The early detection of somatic variants in patients who suffered from IBFMS plays an important role in determining the risk of progression to hematological malignancies. Investigation of clonal evolution using NGS may improve an understanding of mechanisms either malignant transformation or somatic compensation and helps to modify the treatment options.

Biography:

Dr. Raykina studied General Medicine at the Saratov State Medical University named after V. I. Razumovsky, Russia and graduated as MD in 2000. She then finished the hematology clinical residency and after the postgraduate study at the Laboratory of Cell Technologies under the supervision of Prof. Elena Vladimirskaya she received her PhD degree in 2009 at the Scientific Research Institute Of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. In 2015 she became the Head of the Laboratory of Molecular Biology at the Dmitry Rogachev National Research Center, Moscow. She has published more than 50 research articles.