Severe congenital neutropenia (CN) is a pre-leukemia bone marrow failure syndrome presented with profound neutropenia early after birth due to markedly diminished granulocytic differentiation of bone marrow hematopoietic stem and progenitor cells (HSPCs). Patient with severe congenital neutropenia has high risk of leukemia transformation which was estimated to be 22% after 10 years. The risk of leukemia is even more increased in the CN patients with poor G-CSF response. (Skokowa et al. 2017). The identification of acquired nonsense CSF3R mutations is usually the first evidence of leukemogenic transformation. Screening for CSF3R, RUNX1 and other AML/MDS associated mutations (ASXL1, SUZ12, EP300, NPM1) can be helpful for early detection of malignant transformation (Skokowa et al. 2014).
Participation in the initiative is open and free for all members of the EuNET-INNOCHRON
For the enrollment of patients in the study please contact Maksim Klimiankou, PhD Maksim.Klimiankou@med.uni-tuebingen.de.
For question regarding the clinical diagnosis AML/MDS or neutropenia please contact Prof. Dr. Julia Skokowa, Julia.Skokowa@med.uni-tuebingen.de
Inclusion and exclusion criteria for patients in the study
Signed “Informed consent form for adult patients or minor patients' parents (legal Guardian)” is required (the form can be found at https://severe-chronic-neutropenia.org/en/forms).
It is recommended that patient(-s) are registered in the Severe Chronic Neutropenia International Registry using “Registration Form” (the form can be found at https://severe-chronic-neutropenia.org/en/forms).
Samples should be sent to
Maksim Klimiankou, PhD
Division of Translational Oncology
Department of Oncology, Hematology, Clinical Immunology and Rheumatology
University Hospital Tübingen
Otfried-Müller Str. 10
DNA of CN patients will be subjected to panel sequencing using unique molecular identifiers (UMIs). Integration of UMIs in sequencing reads enables strand specific molecular indexing and thus sequencing error correction which allows to catch up to 0.25% variant allele frequency of acquired mutations. Capture probes of the panel cover entire coding sequence of ASXL1, BCOR, BCORL1, CBL, CEBPA, DNMT3A, EP300, EZH2, FLT3, IDH1, IDH2, JAK2, KDM6A, KRAS, NPM1, NRAS, PHF6, PTPN11, RAD21, RUNX1, SETBP1, SF1, SF3B1, SRSF2, STAG2, SUZ12, TET2, TP53, U2AF1, ZRSR2, CSF3R and “hot-spot” positions in the other 209 genes mutated in AML, MDS and ALL. Sequencing will be performed with target raw reads depth 40000x in PE150 mode. The results will be provided as a panel sequencing report with estimation of clinical significance of identified mutations (Figure 1).
Figure1. Project workflow.