OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press9110.17650/1818-8346-2011-6-3-57-64BASIC RESEARCHФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ В ПРАКТИЧЕСКОЙ МЕДИЦИНЕ НА СОВРЕМЕННОМ ЭТАПЕDetection of 11q23 (MLL) rearrangements in infant acute lymphoblastic leukemiaХарактеристика перестроек 11q23 (MLL) у детей первого года жизни с острым лимфобластным лейкозомTsaurG. A.ЦаурГ. А.
Russian Federation
tsaur@mail.ruPopovA. M.ПоповА. М.
Russian Federation
AleynikovaO. V.АлейниковаО. В.
Russian Federation
BoychenkoE. G.БойченкоЭ. Г.
Russian Federation
VerzhbitskayaT. Yu.ВержбицкаяТ. Ю.
Russian Federation
VolochnikE. V.ВолочникЕ. В.
Russian Federation
IvanovaA. S.ИвановаА. С.
Russian Federation
KalennikO. V.КаленникО. В.
Russian Federation
KovalevS. Yu.КовалевС. Ю.
Russian Federation
KondtratchikK. L.КондратчикК. Л.
Russian Federation
KustanovichA. M.КустановичА. М.
Russian Federation
LapotentovaE. S.ЛапотентоваЕ. С.
Russian Federation
LitvinovD. V.ЛитвиновД. В.
Russian Federation
MartynkevichI. S.МартынкевичИ. С.
Russian Federation
MyakovaN. V.МяковаН. В.
Russian Federation
NasedkinaT. V.НаседкинаТ. В.
Russian Federation
OvsepyanV. A.ОвсепянВ. А.
Russian Federation
OlshanskayaYu. V.ОльшанскаяЮ. В.
Russian Federation
PlehanovaO. M.ПлехановаО. М.
Russian Federation
PopaA. V.ПопаА. В.
Russian Federation
RigerT. O.РигерТ. О.
Russian Federation
SavelyevL. I.СавельевЛ. И.
Russian Federation
StrenevaO. V.СтреневаО. В.
Russian Federation
StrigalevaM. V.СтригалеваМ. В.
Russian Federation
ShmunkI. V.ШмункИ. В.
Russian Federation
ShorikovE. V.ШориковЕ. В.
Russian Federation
FechinaL. G.ФечинаЛ. Г.
Russian Federation
Regional Children’s Hospital № 1 Research Institute of Medical Cell TechnologiesГУЗ Областная детская клиническая больница № 1 ГУЗ СО Институт медицинских клеточных технологийBelarusian Research Center for Pediatric Oncology and HematologyГУ Республиканский научно-практический центр детской онкологии и гематологииChildren’s Municipal Hospital № 1ГУЗ Детская городская больница № 1Engelgardt Institute of Molecular Biology Russian Academy of ScienceИнститут молекулярной биологии им. В.А. Энгельгардта РАНB. Eltsyn Ural Federal UniversityФГАОУ ВПО Уральский федеральный университет имени первого Президента России Б.Н. ЕльцинаMorozov Pediatric Municipal Clinical HospitalМорозовская детская городская клиническая больницаFederal Research Institute of Pediatric Hematology, Oncology and ImmunologyФГБУ Федеральный научно-клинический центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева Минздравсоцразвития РоссииRussian Research Institute of Hematology and TransfusiologyФГУ Российский НИИ гематологии и трансфузиологии Федерального медико-биологического агентстваKirov Research Institute of Hematology and TransfusiologyФГУ Кировский НИИ гематологии и переливания крови Федерального медико-биологического агентстваRegional Children’s Hospital № 1ГУЗ Областная детская клиническая больница № 1Ural State Medical AcademyГОУ ВПО Уральская государственная медицинская академияRegional Children’s Hospital № 1 Research Institute of Medical Cell Technologies Ural State Medical AcademyГУЗ Областная детская клиническая больница № 1 ГУЗ СО Институт медицинских клеточных технологий ГОУ ВПО Уральская государственная медицинская академияChelyabinsk Regional Blood Transfusion StationОГУП Челябинская областная станция переливания крови23082011635764230720142011https://oncohematology.abvpress.ru/ongm/article/view/91

117 cases of infant acute lymphoblastic leukemia without Down syndrome (aged from 1 to 365 days) were included in the current study.Rearrangements of 11q23 (MLL) were revealed in 74 (63.2 %) patients. Among this group the most common rearrangement was t(4;11) q21;q23)/MLL-AF4 detected in 63.5 % cases, less frequently was found t(11;19)(q23;p13)/MLL-MLLT1 (in 18.9 % cases), t(10;11) p12;q23)/MLL-MLLT10 and t(1;11)(p32;q23)/ML L-EPS15 (each one in 6.8 %), t(9;11)(p22;q23)/MLL-MLLT3 in 2.7 %. Children under 6 months of age had significantly higher incidence of 11q23 (ML L) rearrangements in comparison with infants olde r than 6 months (84.0 % vs. 47.8 %, p < 0.001). P atients with translocations 11q23 (ML L) more frequently had BI-A LL and less frequently BII-ALL than children without these rearrangements (p < 0.001 f or both). Fusion gene transcript w as sequenced in 26 ML Lrearranged cases. Depending on breakpoint position within ML L and partner genes we detected 7 differ ent types of ML L-AF4 fusion gene transcript, 3 types of MLL-MLLT1, 2 types of MLL-EPS15. The most common fusion site within MLL gene was exon 11, detected in 14 (53.8 %) patients.

acute lymphoblastic leukemiainfantstranslocation 11q23MLL rearrangementsострый лимфобластный лейкоздети первого года жизнитранслокации района 11q23перестройки гена MLL1. Nilson I., Loechner K., Siegler G. et al. Exon/intron structure of ALL1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukemias. Br J Haematol 1996;94(4):966–72.Nilson I., Loechner K., Siegler G. et al. Exon/intron structure of ALL1 (MLL) gene involved in translocations to chromosomal region 11q23 and acute leukemias. Br J Haematol 1996;94(4):966–72.2. Armstrong S., Look A. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005;23:6306–15.Armstrong S., Look A. Molecular genetics of acute lymphoblastic leukemia. J Clin Oncol 2005;23:6306–15.3. Schoch C., Schnittger S., Klaus M. et al. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 2003;102:2395–402.Schoch C., Schnittger S., Klaus M. et al. AML with 11q23/MLL abnormalities as defined by the WHO classification: incidence, partner chromosomes, FAB subtype, age distribution, and prognostic impact in an unselected series of 1897 cytogenetically analyzed AML cases. Blood 2003;102:2395–402.4. Meyer С., Kowarz E., Hofmann J. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23:1490–9.Meyer С., Kowarz E., Hofmann J. et al. New insights to the MLL recombinome of acute leukemias. Leukemia 2009;23:1490–9.5. Reaman G., Zeltzer P., Bleyer W. et al. Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children’s Cancer Study Group. J Clin Oncol 1985;3:1513–21.Reaman G., Zeltzer P., Bleyer W. et al. Acute lymphoblastic leukemia in infants less than one year of age: a cumulative experience of the Children’s Cancer Study Group. J Clin Oncol 1985;3:1513–21.6. Biondi A., Cimino G., Pieters R., Pui C.-H. Biological and therapeutic aspects of infant leukemia. Blood 2000;96:24–33.Biondi A., Cimino G., Pieters R., Pui C.-H. Biological and therapeutic aspects of infant leukemia. Blood 2000;96:24–33.7. Pieters R., Schrappe M., De Lorenzo P. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007;370(9583):240–50.Pieters R., Schrappe M., De Lorenzo P. et al. A treatment protocol for infants younger than 1 year with acute lymphoblastic leukaemia (Interfant-99): an observational study and a multicentre randomised trial. Lancet 2007;370(9583):240–50.8. Tomizawa D., Koh K., Sato T. et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group.Leukemia 2007;11:2258–63.Tomizawa D., Koh K., Sato T. et al. Outcome of risk-based therapy for infant acute lymphoblastic leukemia with or without an MLL gene rearrangement, with emphasis on late effects: a final report of two consecutive studies, MLL96 and MLL98, of the Japan Infant Leukemia Study Group.Leukemia 2007;11:2258–63.9. Chen C-S., Sorensen P., Domer P. at el. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993;81:2386–93.Chen C-S., Sorensen P., Domer P. at el. Molecular rearrangements on chromosome 11q23 predominate in infant acute lymphoblastic leukemia and are associated with specific biologic variables and poor outcome. Blood 1993;81:2386–93.10. Greaves M. Infant leukemia: biology, aetiology and treatment. Leukemia 1996;10:372–7.Greaves M. Infant leukemia: biology, aetiology and treatment. Leukemia 1996;10:372–7.11. Isoyama K., Eguchi M., Hibi S. et al. Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 2002;118:999–1010.Isoyama K., Eguchi M., Hibi S. et al. Risk-directed treatment of infant acute lymphoblastic leukaemia based on early assessment of MLL gene status: results of the Japan Infant Leukaemia Study (MLL96). Br J Haematol 2002;118:999–1010.12. Pui C.-H., Chessells J., Camitta B. et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 2003;17:700–6.Pui C.-H., Chessells J., Camitta B. et al. Clinical heterogeneity in childhood acute lymphoblastic leukemia with 11q23 rearrangements. Leukemia 2003;17:700–6.13. Hilden J., Dinndorf P., Meerbaum S. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood 2006;108:441–51.Hilden J., Dinndorf P., Meerbaum S. et al. Analysis of prognostic factors of acute lymphoblastic leukemia in infants: report on CCG 1953 from the Children’s Oncology Group. Blood 2006;108:441–51.14. Cimino G., Rapanotti M., Sprovieri T., Elia L. ALL1 gene alterations in acute leukemia: biological and clinical aspects. Haematologica 1998;83:350–7.Cimino G., Rapanotti M., Sprovieri T., Elia L. ALL1 gene alterations in acute leukemia: biological and clinical aspects. Haematologica 1998;83:350–7.15. Gale K., Ford A., Repp R. et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci USA 1997;94:13950–4.Gale K., Ford A., Repp R. et al. Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots. Proc Natl Acad Sci USA 1997;94:13950–4.16. Slany R. The molecular biology of mixed lineage leukemia. Haematologica 2009;94:984–93.Slany R. The molecular biology of mixed lineage leukemia. Haematologica 2009;94:984–93.17. Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood 2007;110(11) :832А.Abstr. 2828.Fechina L., Shorikov E., Tsaur G. et al. Contribution of all-trans retinoic acid to improved early relapse-free outcome in infant acute lymphoblastic leukemia comparing to the chemotherapy alone. Blood 2007;110(11) :832А.Abstr. 2828.18. Tsaur G., Popov A., Nasedkina T. et al. Minimal residual disease monitoring by quantification of fusion gene transcript in infant with MLL-rearranged acute lymphoblastic leukemia by MLL-Baby protocol. Blood 2010;116(21):1126. Abstr. 2731.Tsaur G., Popov A., Nasedkina T. et al. Minimal residual disease monitoring by quantification of fusion gene transcript in infant with MLL-rearranged acute lymphoblastic leukemia by MLL-Baby protocol. Blood 2010;116(21):1126. Abstr. 2731.19. Цаур Г.А., Наседкина Т.В., Попов А.М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни с острым лимфобластным лейкозом. Онкогематология 2010;2:46–54.Цаур Г.А., Наседкина Т.В., Попов А.М. и др. Время достижения молекулярной ремиссии как фактор прогноза у детей первого года жизни с острым лимфобластным лейкозом. Онкогематология 2010;2:46–54.20. Bennett J., Catovsky D., Daniel M. et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976;33:451–8.Bennett J., Catovsky D., Daniel M. et al. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 1976;33:451–8.21. Bene M., Castoldi G., Knapp W. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995;9(10):1783–6.Bene M., Castoldi G., Knapp W. et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia 1995;9(10):1783–6.22. ISCN (2005): An International System for Human Cytogenetic Nomenclature (2005). Editors: Shaffer L.G., Tommerup N. Karger, Basel, Switzerland, 2005.ISCN (2005): An International System for Human Cytogenetic Nomenclature (2005). Editors: Shaffer L.G., Tommerup N. Karger, Basel, Switzerland, 2005.23. Borkhardt A., Repp R., Haupt E. et al. Molecular analysis of MLL/AF4 recombination in infant acute lymphoblastic leukemia. Leukemia 1994;8:549–53.Borkhardt A., Repp R., Haupt E. et al. Molecular analysis of MLL/AF4 recombination in infant acute lymphoblastic leukemia. Leukemia 1994;8:549–53.24. Pallisgaard N., Hokland P., Riishoj D. et al. Multiplex reverse transcriptionpolymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia.Pallisgaard N., Hokland P., Riishoj D. et al. Multiplex reverse transcriptionpolymerase chain reaction for simultaneous screening of 29 translocations and chromosomal aberrations in acute leukemia.Blood 1998;92:574–88.25. Dongen van J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999;13:1901–18.Dongen van J., Macintyre E., Gabert J. et al. Standardized RT-PCR analysis of fusion gene transcripts from chromosome aberrations in acute leukemia for detection of minimal residual disease. Leukemia 1999;13:1901–18.26. Emerenciano M., Arias D., Coser V. et al. Molecular cytogenetic findings of acute leukemia included in the Brazilian collaborative study group of infant acute leukemia. Pediatr Blood Cancer 2006;47:549–54.Emerenciano M., Arias D., Coser V. et al. Molecular cytogenetic findings of acute leukemia included in the Brazilian collaborative study group of infant acute leukemia. Pediatr Blood Cancer 2006;47:549–54.27. Borkhardt A., Wuchter C., Viehmann S. et al. Infant acute lymphoblastic leukemia — combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia 2002;16:1685–90.Borkhardt A., Wuchter C., Viehmann S. et al. Infant acute lymphoblastic leukemia — combined cytogenetic, immunophenotypical and molecular analysis of 77 cases. Leukemia 2002;16:1685–90.28. Chessells J., Harrison C., Kempski H. et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party. Leukemia 2002;16:776–84.Chessells J., Harrison C., Kempski H. et al. Clinical features, cytogenetics and outcome in acute lymphoblastic and myeloid leukaemia of infancy: report from the MRC Childhood Leukaemia working party. Leukemia 2002;16:776–84.29. Bernard O., Mauchauffe M., Mecucci C. et al. A novel gene, AF-lp, fused to HRX in t(1;11)(p32;q23) is not related to AF-4, AF-9 nor ENL. Oncogene 1994;9:1039–45.Bernard O., Mauchauffe M., Mecucci C. et al. A novel gene, AF-lp, fused to HRX in t(1;11)(p32;q23) is not related to AF-4, AF-9 nor ENL. Oncogene 1994;9:1039–45.30. DiMartino J., Cleary M. MLL rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 1999;106:614–26.DiMartino J., Cleary M. MLL rearrangements in haematological malignancies: lessons from clinical and biological studies. Br J Haematol 1999;106:614–26.31. Harrison C., Cuneo A., Clark R. et al. Ten novel 11q23 chromosomal partner sites. Leukemia 1998;12:811–22.Harrison C., Cuneo A., Clark R. et al. Ten novel 11q23 chromosomal partner sites. Leukemia 1998;12:811–22.32. Jansen M., Corral L., van der Velden V. et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 2007;21:633–41.Jansen M., Corral L., van der Velden V. et al. Immunobiological diversity in infant acute lymphoblastic leukemia is related to the occurrence and type of MLL gene rearrangement. Leukemia 2007;21:633–41.33. Lightfoot T. Aetiology of Childhood Leukemia. Bioelectromagnetics 2005; Suppl 7:5–11.Lightfoot T. Aetiology of Childhood Leukemia. Bioelectromagnetics 2005; Suppl 7:5–11.34. Mathew S., Behm F., Dalton J., Raimondi S. Comparison of cytogenetics, Southern blotting and fluorescence in situ hybridization as methods for detecting MLL gene rearrangements in children with acute leukemia and with 11q23 abnormalities. Leukemia 1999;13:1713–20.Mathew S., Behm F., Dalton J., Raimondi S. Comparison of cytogenetics, Southern blotting and fluorescence in situ hybridization as methods for detecting MLL gene rearrangements in children with acute leukemia and with 11q23 abnormalities. Leukemia 1999;13:1713–20.35. Burmeister T., Meyer C., Schwartz S. et al. The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group. Blood 2009; 113:4011–5.Burmeister T., Meyer C., Schwartz S. et al. The MLL recombinome of adult CD10-negative B-cell precursor acute lymphoblastic leukemia: results from the GMALL study group. Blood 2009; 113:4011–5.36. Pui C.-H., Gaynon P., Boyett J. et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002;359:1909–15.Pui C.-H., Gaynon P., Boyett J. et al. Outcome of treatment in childhood acute lymphoblastic leukaemia with rearrangements of the 11q23 chromosomal region. Lancet 2002;359:1909–15.37. Silverman L., McLean T., Gelber R. et al. Intensified therapy for infants with acute lymphoblastic leukemia results from the Dana-Farber Cancer Institute Consortium. Cancer 1997;80:2285–95.Silverman L., McLean T., Gelber R. et al. Intensified therapy for infants with acute lymphoblastic leukemia results from the Dana-Farber Cancer Institute Consortium. Cancer 1997;80:2285–95.38. Dordelmann M., Reiter A., Borkhardt A. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999;94:1209–17.Dordelmann M., Reiter A., Borkhardt A. et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood 1999;94:1209–17.39. Velden van der V., Corall L., Valsecchi M. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009;23:1073–9.Velden van der V., Corall L., Valsecchi M. et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia 2009;23:1073–9.40. Pui C.-H., Frankel L., Carroll A. et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): A collaborative study of 40 cases.Blood 1991;77:440–7.Pui C.-H., Frankel L., Carroll A. et al. Clinical characteristics and treatment outcome of childhood acute lymphoblastic leukemia with the t(4;11)(q21;q23): A collaborative study of 40 cases.Blood 1991;77:440–7.41. Mann G., Cazzaniga G., van der Velden V. et al. Acute lymphoblastic leukemia with t(4;11) in children one year and older: the ‘big sister’ of the infant disease? Leukemia 2007;21:642–6.Mann G., Cazzaniga G., van der Velden V. et al. Acute lymphoblastic leukemia with t(4;11) in children one year and older: the ‘big sister’ of the infant disease? Leukemia 2007;21:642–6.42. Linden van der M., Valsecchi M., De Lorenzo P. et al Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 2009; 114:3764–8.Linden van der M., Valsecchi M., De Lorenzo P. et al Outcome of congenital acute lymphoblastic leukemia treated on the Interfant-99 protocol. Blood 2009; 114:3764–8.43. Pui C.-H., Ribeiro R., Campana D. et al. Prognostic factors in the acute lymphoid and myeloid leukemias of infants.Leukemia 1996;10:952–6.Pui C.-H., Ribeiro R., Campana D. et al. Prognostic factors in the acute lymphoid and myeloid leukemias of infants.Leukemia 1996;10:952–6.