г ема т о л о г и я УДК 616.155.394-053.1-039.38:616.155.392]-092 Mechanisms of leukemogenesis in severe congenital neutropenia patients J.Skokowa1 , K.Welte2 1University Clinics Tьbingen, Tьbingen, Germany; 2Hannover Medical School, Hannover, Germany Congenital neutropenia (CN) is a rare pre-leukemic bone marrow failure syndrome with a 20% risk of evolving into acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or rarely in acute lymphoblastic leukemia. <...> Approximately 70–80% of CN patients who develop AML or MDS acquire heterozygous granulocyte colony-stimulating factor (G-CSF) receptor (CSF3R) mutations, independent of the genetic subtype, suggesting that these mutations are involved in leukemogenesis. <...> We investigated leukemia-associated patterns of mutation acquisition in 31 CN patients who developed MDS or leukemia using next-generation sequencing. <...> Other leukemia-associated mutations in patients with RUNX1 mutations were less frequent, and included EP300 (three patients), FLT3-ITD (two patients), CBL (one patient), and SUZ12 (one patient). <...> Key words: congenital neutropenia, acute myeloid leukemia, mutations, granulocyte colony-stimulating factor receptor, CSF3R gene, RUNX1 gene evere congenital neutropenia (CN) is a heterogeneous bone marrow failure syndrome characterized by severe neutropenia (blood neutrophil counts less than 0.5 Ч 109 S /l) and maturation arrest of myelopoiesis at the level of the promyelocytes/myelocytes [1]. <...> Autosomal-dominant and sporadic CN cases are predominantly attributable to mutations in ELANE, the gene encoding neutrophil elastase [2]. <...> Several other genetic mutations, including those in HAX1 (HCLS1-associated protein X-1), G6PC3 (glucose 6 phosphatase, catalytic, 3), GFI1 (growth factor independent 1 transcription repressor) and WAS (Wiskott–Aldrich syndrome gene) have been described in patients with CN [3–6]. <...> The majority of CN patients benefit from treatment with granulocyte colonystimulating factor (G-CSF) [7]. <...> Common pathological mechanisms for the maturation arrest of myeloid development in these patients include the lack of myeloid-specific transcription factors, such as LEF-1 (lymphoid enhancer-binding factor 1) and C/EBP α (CCAAT/ /enhancer binding protein α), and defective G-CSF signaling [8]. <...> As J.Welch, et al <...>