Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children14710.24287/1726-1708-2016-15-1-41-45ИММУНОЛОГИЯGenetic predictors of an unfavorable course of severe congenital neutropenia in patients with ELANE gene mutationГенетические предикторы неблагоприятного течения тяжелой врожденной нейтропении у пациентов с мутацией в гене ELANEDeordievaEkaterina A.ДеордиеваЕкатерина Анатольевна
Russian Federation
deor2005@yandex.ruVarlamovaTatyana V.ВарламоваТатьяна Владимировна
Russian Federation
varltatwell@mail.ruRaikinaElena V.РайкинаЕлена Владиславовна
Russian Federation
e_raikina@inbox.ruShcherbinaAnna Yu.ЩербинаАнна Юрьевна
Russian Federation
shcher26@hotmail.comFederal Research Center of Pediatric Hematology, Oncology, and Immunology named after Dmitry RogachevФедеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева Минздрава России19032016151414519092018Copyright ©; 2016, «D. Rogachev NMRCPHOI»Copyright ©; 2016, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2016«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/147

Severe congenital neutropenia (SCN) is a rare genetically determined disease with disruption of granulocyte maturation in bone marrow, resulting in a high risk of life-threatening infections. The disease is caused by ELANE gene mutation in the majority (60-80%) of patients. Our study confirms the data of the Severe Congenital Neutropenia International Registry: we have demonstrated an association of ELANE gene mutations (in C151 and G214 positions) with a particularly severe disease course, manifesting by resistance to therapy with granulocyte colony-stimulating factor and the development of myelodysplastic syndrome.

Тяжелая врожденная нейтропения (ТВН) является редким генетически обусловленным заболеванием с обрывом созревания гранулоцитов в костном мозге и, как следствие, высоким риском развития угрожающих жизни инфекций. У большей части пациентов (60-80%) заболевание вызвано мутацией в гене ELANE. В подтверждение ранее опубликованных данных Международного регистра ТВН (Severe Congenital Neutropenia International Registry) мы показали ассоциацию конкретных мутаций в гене ELANE (в позициях C151 и G214) с особо тяжелым течением заболевания, что проявляется резистентностью к терапии гранулоцитарным колониестимулирующим фактором и развитием миелодис-пластического синдрома.

детиврожденная нейтропенияциклическая нейтропениямутация в гене ELANEтяжесть течениягранулоцитарный колониестимулирующий факторострый миелоидный лейкозмиелодиспластический синдромchildrencongenital neutropeniacyclic neutropeniaELANE gene mutationsevere coursegranulocyte colony-stimulating factoracute myeloid leukemiamyelodysplastic syndromeDale DC. ELANE-related neutropenia [Internet]. University of Washington, Seattle (WA): Gene ReviewsTM: 2002. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1533/[updated 14 July 2011].Horwitz M, Benson KF, Person RE, Aprikyan AG, Dale DC. Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic haematopoiesis. Nat Genet. 1999; 23(4): 433-6.Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, Bonilla MA, et al. Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood. 2000; 96(7): 2317-22.Dale DC, Bolyard AA, Aprikyan A. Cyclic neutropenia. Semin Hematol. 2002; 39(2): 89-94.Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol. 2006; 43(3): 189-95.Ancliff PJ, Gale RE, Liesner R, Hann IM, Linch DC. Mutations in the ELA2 gene encoding neutrophil elastase are present in most patients with sporadic severe congenital neutropenia but only in some patients with the familial form of the disease. Blood. 2001; 98(9): 2645-50.Köllner I, Sodeik B, Schreek S, Heyn H, von Neuhoff N, Germeshausen M, et al. Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response. Blood. 2006; 108(2): 493-500.Grenda DS, Murakami M, Ghatak J, Xia J, Boxer LA, Dale D, et al. Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis. Blood. 2007; 110(13): 4179-87.Nanua S, Murakami M, Xia J, Grenda DS, Woloszynek J, Strand M, et al. Activation of the unfolded protein response is associated with impaired granulopoiesis in transgenic mice expressing mutant Elane. Blood. 2011; 117(13): 3539-47.Borregaard N. Severe congenital neutropenia: new lane for ELANE. Blood. 2014; 123(4): 462-3.Dale DC, Cottle TE, Fier CJ, Bolyard AA, Bonilla MA, Boxer LA, et al. Severe chronic neutropenia: treatment and follow-up of patients in the Severe Chronic Neutropenia International Registry. Am J Hematol. 2003; 72(2): 82-93.Rosenberg PS, Zeidler C, Bolyard AA, Alter BP, Bonilla MA, Boxer LA, et al. Stable long-term risk of leukaemia in patients with severe congenital neutropenia maintained on G-CSF therapy. Br J Haematol. 2010; 150(2): 196-9.Beekman R, Touw IP. G-CSF and its receptor in myeloid malignancy. Blood. 2010; 115(25): 5131-6.Link DC, Kunter G, Kasai Y, Zhao Y, Miner T, McLellan MD, et al. Distinct patterns of mutations occurring in de novo AML versus AML arising in the setting of severe congenital neutropenia. Blood. 2007; 110(5): 1648-55.Skokowa J, Steinemann D, Katsman-Kuipers JE, Zeidler C, Klimenkova O, Klimiankou M, et al. Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood. 2014; 123(14): 2229-37.Horwitz MS, Corey SJ, Grimes HL, Tidwell T. ELANE mutations in cyclic and severe congenital neutropenia: genetics and pathophysiology. Hematol Oncol Clin North Am. 2013; 27(1): 19-41.Germeshausen M, Deerberg S, Peter Y, Reimer C, Kratz CP, Ballmaier M. The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia. Hum Mutat. 2013; 34(6): 905-14.Bellanné-Chantelot C, Clauin S, Leblanc T, Cassinat B, Rodrigues-Lima F, Beaufils S, et al. Mutations in the ELA2 gene correlate with more severe expression of neutropenia: a study of 81 patients from the French Neutropenia Register. Blood. 2004; 103(11): 4119-25.Makaryan V, Zeidler C, Bolyard AA, Skokowa J, Rodger E, Kelley ML, et al. The diversity of mutations and clinical outcomes for ELANE-associated neutropenia. Curr Opin Hematol. 2015; 22(1): 3-11.