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Возможности эпигенетической терапии острых миелоидных лейкозов у детей
Возможности эпигенетической терапии острых миелоидных лейкозов у детей
Серегин Г.З., Лифшиц А.В., Алескерова Г.А., Валиев Т.Т. Возможности эпигенетической терапии острых миелоидных лейкозов у детей. Современная Онкология. 2019; 21 (4): 15–20. DOI: 10.26442/18151434.2019.4.190712
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Аннотация
Результаты лечения острых миелоидных лейкозов (ОМЛ) у детей при использовании современных программ терапии позволяют достичь многолетней общей выживаемости лишь у 65–70% больных, показатели бессобытийной выживаемости ниже и составляют около 55%. Существенным прогрессом в лечении ОМЛ у детей стала разработка протоколов программного высокоинтенсивного лечения, в основе которого лежит «блоковый» принцип с последующей длительной поддерживающей терапией. По мере совершенствования сопроводительного лечения стало возможным увеличение доз химиопрепаратов, что способствовало росту эффективности проводимого лечения. Но к настоящему времени дозы и режимы введения используемых препаратов в лечении ОМЛ приблизились к максимально переносимым, что диктует необходимость поиска новых терапевтических воздействий на опухолевую клетку. Успехи фундаментальной онкологии позволили определить ключевые маркеры ОМЛ и синтезировать ряд таргетных препаратов, обладающих направленным действием. Изучение эпигенетических процессов, лежащих в основе лейкозогенеза, позволило выделить ключевые события, которые стали мишенью для таргетного воздействия – метилирование ДНК и деацетилирование гистонов. В настоящей работе представлены результаты использования эпигенетических препаратов в лечении ОМЛ у детей, приведены возможности включения эпигенетических агентов в стандартные протоколы полихимиотерапии.
Ключевые слова: эпигенетические препараты, метилирование, деацетилирование, острые миелоидные лейкозы, лечение, дети.
Key words: epigenetic drugs, methylation, deacetylation, acute myeloid leukemia, treatment, children.
Ключевые слова: эпигенетические препараты, метилирование, деацетилирование, острые миелоидные лейкозы, лечение, дети.
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Key words: epigenetic drugs, methylation, deacetylation, acute myeloid leukemia, treatment, children.
Полный текст
Список литературы
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36. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 2014; 13: 337–35.
37. Filippakopoulos P et al. Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family. Cell 2012; 149 (1): 214–31.
38. Dawson MA et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478 (7370): 529–33.
39. Zuber J et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; p. 1–7.
40. Shiba N et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br J Haematol 2016; 175 (3): 476–89.
41. Tao Y-F. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia. BMC Cancer 2015; p. 1–13.
42. Wong IHN et al. Aberrant < em> p15< /em> promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000; 95 (6): 1942.
43. Dombret H et al. International phase 3 study of azacitidine vs conventionalcare regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (3): 291–9.
44. Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: arandomised, open-label, phase III study. Lancet Oncol 2009; 10 (3): 223–32.
45. Phillips CL et al. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol 2013; 161 (3): 406–10.
46. Gore L et al. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenet 2017; 9: 108.
47. Sun W et al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium. Blood 2018; 131 (10): 1145–8.
48. Platzbecker U et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2011; 26 (3): 381–9.
49. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127 (1): 71–8.
50. Stein EM et al. Enasidenib in mutant IDH2relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (6): 722–31.
51. Andersson AK et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 2011; 25 (10): 1570–7.
52. Papaemmanuil E et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. New Engl J Med 2016; 374 (23): 2209–21.
53. Chan SM et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Med 2015; 21 (2): 178–84.
54. Qi J et al. HDAC8 Inhibition Specifically Targets Inv (16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 2015; 17 (5): 597–610.
55. Garcia-Manero G et al. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol 2012; 30 (18): 2204–10.
56. Wang J et al. Inhibitors of Histone Deacetylase Relieve ETO-mediated Repression and Induce Differentiation of AML1-ETO Leukemia Cells. Cancer Res 1999; 59 (12): 2766.
57. Kuendgen A et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acutemyeloid leukemia. Cancer 2006; 106 (1): 112–9.
58. Gelmetti V et al. Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO. Mol Cell Biol 1998; 18 (12): 7185–91.
59. Byrd JC. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100 (13): 4325–36.
60. Rubnitz JE et al. Characteristics and outcome of t (8;21)-positive childhood acute myeloid leukemia: a single institution’s experience. Leukemia 2002; 16 (10): 2072–7.
61. Balgobind BV et al. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia. Leukemia 2011; 25 (8): 1239–48.
62. Karol SE et al. Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy. Br J Haematol 2014; 168 (1): 94–101.
63. Shukla N et al. Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood 2016; 128 (22): 2780.
64. Liu W et al. DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy. PLoS One 2014; 9 (5): e98270–11
2. Genovese G et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferredfrom Blood DNA Sequence. New Engl J Med 2014; 371 (26): 2477–87.
3. Jaiswal S et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. New Engl J Med 2014; 371 (26): 2488–98.
4. Xie M et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nature Med 2014; 20 (12):1472–8.
5. The Cancer Genome Atlas Research Network 2013a.
6. Bewersdorf JP. Epigenetic therapy combinations in acutemyeloid leukemia: what are the options? Ther Adv Hematol 2019; 10: 2040620718816698. DOI: 10.1177/2040620718816698
7. Ley TJ, Ding L, Walter MJ et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–33.
8. Delhommeau F, Dupont S, Della Valle V et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–301.
9. Paschka P, Schlenk RF, Gaidzik VI et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010; 28: 3636–43.
10. Challen GA et al. DNMT3A is essential for hematopoietic stem cell differentiation. Nature Genet 2011; 44 (1): 23–31.
11. Guryanova OA et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nature Med 2016; 22 (12): 1488–95.
12. Shlush LI et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014: 1–14.
13. Li Z et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011; 118 (17): 4509–18.
14. Patel JP et al. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. New Engl J Med 2012; 366 (12): 1079–89.
15. Abdel-Wahab O et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009: 114 (1): 144–7.
16. Rasmussen KD et al. Loss of TET2in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Development 2015; 29 (9): 910–22.
17. Ward PS et al. The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate. Cancer Cell 2010; 17 (3): 225–34.
18. Dang L et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274): 739–44.
19. Valerio DG et al. Mapping epigenetic regulator gene mutations in сytogenetically normal pediatric acute myeloid leukemia. Haematologica 2014; 99 (8): e130–e132.
20. Liang DC et al. Cooperating gene mutations in childhood acute myeloidleukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. Blood 2013; 121 (15): 2988–95.
21. Damm F, Thol F, Hollink I et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups. Leukemia 2011; 25 (11): 1704–10. DOI: 10.1038/leu.2011.142
22. Eibrink MM, Zwaan CM, de Haas V et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhooAML: a study of the AML– BFM and DCOG study groups. Leukemia 2011a; 25 (11): 1704–10.
23. Marcucci G et al. IDH1and IDH2Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. JCO 2010; 28 (14): 2348–55.
24. Gaidzik VI et al. TET2 Mutations in Acute Myeloid Leukemia (AML): Results From a Comprehensive Genetic and Clinical Analysis of the AML Study Group. J Clin Oncol 2012; 30 (12): 1350–7.
25. Bas J. Wouters, Ruud Delwel; Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016; 127 (1): 42–52
26. Grignani F et al. Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391 (6669): 815–8.
27. Izutsu K et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood 2001; 97 (9): 2815–22.
28. Fazi F et al. Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood 2007; 109 (10): 4432–40.
29. Fong CY, Morison J, Dawson MA. Epigenetics in the hematologic malignancies. Haematologica 2014; 99 (12): 1772–83.
30. Slany RK. The molecular biology of mixed lineage leukemia. Haematologica 2009; 94 (7): 984–93.
31. Chaudhury SS et al. Insights into cell ontogeny, age, and acute myeloid leukemia. Exper Hematol 2015; 43 (9): 745–55.
32. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev Cancer 2007; 7 (11): 823–33.
33. Schoch C. 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 (7): 2395–402.
34. Grimwade D et al. The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial. Blood 1998; 92 (7): 2322.
35. Harrison CJ et al. Cytogenetics of Childhood Acute Myeloid Leukemia: United Kingdom Medical Research Council Treatment Trials AML 10 and 12. JCO 2010; 28 (16): 2674–81.
36. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 2014; 13: 337–35.
37. Filippakopoulos P et al. Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family. Cell 2012; 149 (1): 214–31.
38. Dawson MA et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478 (7370): 529–33.
39. Zuber J et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; p. 1–7.
40. Shiba N et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br J Haematol 2016; 175 (3): 476–89.
41. Tao Y-F. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia. BMC Cancer 2015; p. 1–13.
42. Wong IHN et al. Aberrant < em> p15< /em> promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000; 95 (6): 1942.
43. Dombret H et al. International phase 3 study of azacitidine vs conventionalcare regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (3): 291–9.
44. Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: arandomised, open-label, phase III study. Lancet Oncol 2009; 10 (3): 223–32.
45. Phillips CL et al. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol 2013; 161 (3): 406–10.
46. Gore L et al. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenet 2017; 9: 108.
47. Sun W et al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium. Blood 2018; 131 (10): 1145–8.
48. Platzbecker U et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2011; 26 (3): 381–9.
49. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127 (1): 71–8.
50. Stein EM et al. Enasidenib in mutant IDH2relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (6): 722–31.
51. Andersson AK et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 2011; 25 (10): 1570–7.
52. Papaemmanuil E et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. New Engl J Med 2016; 374 (23): 2209–21.
53. Chan SM et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Med 2015; 21 (2): 178–84.
54. Qi J et al. HDAC8 Inhibition Specifically Targets Inv (16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 2015; 17 (5): 597–610.
55. Garcia-Manero G et al. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol 2012; 30 (18): 2204–10.
56. Wang J et al. Inhibitors of Histone Deacetylase Relieve ETO-mediated Repression and Induce Differentiation of AML1-ETO Leukemia Cells. Cancer Res 1999; 59 (12): 2766.
57. Kuendgen A et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acutemyeloid leukemia. Cancer 2006; 106 (1): 112–9.
58. Gelmetti V et al. Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO. Mol Cell Biol 1998; 18 (12): 7185–91.
59. Byrd JC. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100 (13): 4325–36.
60. Rubnitz JE et al. Characteristics and outcome of t (8;21)-positive childhood acute myeloid leukemia: a single institution’s experience. Leukemia 2002; 16 (10): 2072–7.
61. Balgobind BV et al. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia. Leukemia 2011; 25 (8): 1239–48.
62. Karol SE et al. Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy. Br J Haematol 2014; 168 (1): 94–101.
63. Shukla N et al. Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood 2016; 128 (22): 2780.
64. Liu W et al. DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy. PLoS One 2014; 9 (5): e98270–11.
2. Genovese G et al. Clonal Hematopoiesis and Blood-Cancer Risk Inferredfrom Blood DNA Sequence. New Engl J Med 2014; 371 (26): 2477–87.
3. Jaiswal S et al. Age-Related Clonal Hematopoiesis Associated with Adverse Outcomes. New Engl J Med 2014; 371 (26): 2488–98.
4. Xie M et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nature Med 2014; 20 (12):1472–8.
5. The Cancer Genome Atlas Research Network 2013a.
6. Bewersdorf JP. Epigenetic therapy combinations in acutemyeloid leukemia: what are the options? Ther Adv Hematol 2019; 10: 2040620718816698. DOI: 10.1177/2040620718816698
7. Ley TJ, Ding L, Walter MJ et al. DNMT3A mutations in acute myeloid leukemia. N Engl J Med 2010; 363: 2424–33.
8. Delhommeau F, Dupont S, Della Valle V et al. Mutation in TET2 in myeloid cancers. N Engl J Med 2009; 360: 2289–301.
9. Paschka P, Schlenk RF, Gaidzik VI et al. IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 2010; 28: 3636–43.
10. Challen GA et al. DNMT3A is essential for hematopoietic stem cell differentiation. Nature Genet 2011; 44 (1): 23–31.
11. Guryanova OA et al. DNMT3A mutations promote anthracycline resistance in acute myeloid leukemia via impaired nucleosome remodeling. Nature Med 2016; 22 (12): 1488–95.
12. Shlush LI et al. Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia. Nature 2014: 1–14.
13. Li Z et al. Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood 2011; 118 (17): 4509–18.
14. Patel JP et al. Prognostic Relevance of Integrated Genetic Profiling in Acute Myeloid Leukemia. New Engl J Med 2012; 366 (12): 1079–89.
15. Abdel-Wahab O et al. Genetic characterization of TET1, TET2, and TET3 alterations in myeloid malignancies. Blood 2009: 114 (1): 144–7.
16. Rasmussen KD et al. Loss of TET2in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Development 2015; 29 (9): 910–22.
17. Ward PS et al. The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-Hydroxyglutarate. Cancer Cell 2010; 17 (3): 225–34.
18. Dang L et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 2009; 462 (7274): 739–44.
19. Valerio DG et al. Mapping epigenetic regulator gene mutations in сytogenetically normal pediatric acute myeloid leukemia. Haematologica 2014; 99 (8): e130–e132.
20. Liang DC et al. Cooperating gene mutations in childhood acute myeloidleukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. Blood 2013; 121 (15): 2988–95.
21. Damm F, Thol F, Hollink I et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhood AML: a study of the AML-BFM and DCOG study groups. Leukemia 2011; 25 (11): 1704–10. DOI: 10.1038/leu.2011.142
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23. Marcucci G et al. IDH1and IDH2Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. JCO 2010; 28 (14): 2348–55.
24. Gaidzik VI et al. TET2 Mutations in Acute Myeloid Leukemia (AML): Results From a Comprehensive Genetic and Clinical Analysis of the AML Study Group. J Clin Oncol 2012; 30 (12): 1350–7.
25. Bas J. Wouters, Ruud Delwel; Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016; 127 (1): 42–52
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41. Tao Y-F. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia. BMC Cancer 2015; p. 1–13.
42. Wong IHN et al. Aberrant < em> p15< /em> promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000; 95 (6): 1942.
43. Dombret H et al. International phase 3 study of azacitidine vs conventionalcare regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (3): 291–9.
44. Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: arandomised, open-label, phase III study. Lancet Oncol 2009; 10 (3): 223–32.
45. Phillips CL et al. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol 2013; 161 (3): 406–10.
46. Gore L et al. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenet 2017; 9: 108.
47. Sun W et al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium. Blood 2018; 131 (10): 1145–8.
48. Platzbecker U et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2011; 26 (3): 381–9.
49. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127 (1): 71–8.
50. Stein EM et al. Enasidenib in mutant IDH2relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (6): 722–31.
51. Andersson AK et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 2011; 25 (10): 1570–7.
52. Papaemmanuil E et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. New Engl J Med 2016; 374 (23): 2209–21.
53. Chan SM et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Med 2015; 21 (2): 178–84.
54. Qi J et al. HDAC8 Inhibition Specifically Targets Inv (16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 2015; 17 (5): 597–610.
55. Garcia-Manero G et al. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol 2012; 30 (18): 2204–10.
56. Wang J et al. Inhibitors of Histone Deacetylase Relieve ETO-mediated Repression and Induce Differentiation of AML1-ETO Leukemia Cells. Cancer Res 1999; 59 (12): 2766.
57. Kuendgen A et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acutemyeloid leukemia. Cancer 2006; 106 (1): 112–9.
58. Gelmetti V et al. Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO. Mol Cell Biol 1998; 18 (12): 7185–91.
59. Byrd JC. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100 (13): 4325–36.
60. Rubnitz JE et al. Characteristics and outcome of t (8;21)-positive childhood acute myeloid leukemia: a single institution’s experience. Leukemia 2002; 16 (10): 2072–7.
61. Balgobind BV et al. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia. Leukemia 2011; 25 (8): 1239–48.
62. Karol SE et al. Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy. Br J Haematol 2014; 168 (1): 94–101.
63. Shukla N et al. Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood 2016; 128 (22): 2780.
64. Liu W et al. DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy. PLoS One 2014; 9 (5): e98270–11
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22. Eibrink MM, Zwaan CM, de Haas V et al. Prevalence and prognostic value of IDH1 and IDH2 mutations in childhooAML: a study of the AML– BFM and DCOG study groups. Leukemia 2011a; 25 (11): 1704–10.
23. Marcucci G et al. IDH1and IDH2Gene Mutations Identify Novel Molecular Subsets Within De Novo Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study. JCO 2010; 28 (14): 2348–55.
24. Gaidzik VI et al. TET2 Mutations in Acute Myeloid Leukemia (AML): Results From a Comprehensive Genetic and Clinical Analysis of the AML Study Group. J Clin Oncol 2012; 30 (12): 1350–7.
25. Bas J. Wouters, Ruud Delwel; Epigenetics and approaches to targeted epigenetic therapy in acute myeloid leukemia. Blood 2016; 127 (1): 42–52
26. Grignani F et al. Fusion proteins of the retinoic acid receptor-a recruit histone deacetylase in promyelocytic leukaemia. Nature 1998; 391 (6669): 815–8.
27. Izutsu K et al. The corepressor CtBP interacts with Evi-1 to repress transforming growth factor beta signaling. Blood 2001; 97 (9): 2815–22.
28. Fazi F et al. Heterochromatic gene repression of the retinoic acid pathway in acute myeloid leukemia. Blood 2007; 109 (10): 4432–40.
29. Fong CY, Morison J, Dawson MA. Epigenetics in the hematologic malignancies. Haematologica 2014; 99 (12): 1772–83.
30. Slany RK. The molecular biology of mixed lineage leukemia. Haematologica 2009; 94 (7): 984–93.
31. Chaudhury SS et al. Insights into cell ontogeny, age, and acute myeloid leukemia. Exper Hematol 2015; 43 (9): 745–55.
32. Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nature Rev Cancer 2007; 7 (11): 823–33.
33. Schoch C. 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 (7): 2395–402.
34. Grimwade D et al. The Importance of Diagnostic Cytogenetics on Outcome in AML: Analysis of 1,612 Patients Entered Into the MRC AML 10 Trial. Blood 1998; 92 (7): 2322.
35. Harrison CJ et al. Cytogenetics of Childhood Acute Myeloid Leukemia: United Kingdom Medical Research Council Treatment Trials AML 10 and 12. JCO 2010; 28 (16): 2674–81.
36. Filippakopoulos P, Knapp S. Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 2014; 13: 337–35.
37. Filippakopoulos P et al. Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family. Cell 2012; 149 (1): 214–31.
38. Dawson MA et al. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 2011; 478 (7370): 529–33.
39. Zuber J et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; p. 1–7.
40. Shiba N et al. Whole-exome sequencing reveals the spectrum of gene mutations and the clonal evolution patterns in paediatric acute myeloid leukaemia. Br J Haematol 2016; 175 (3): 476–89.
41. Tao Y-F. Hypermethylation of the GATA binding protein 4 (GATA4) promoter in Chinese pediatric acute myeloid leukemia. BMC Cancer 2015; p. 1–13.
42. Wong IHN et al. Aberrant < em> p15< /em> promoter methylation in adult and childhood acute leukemias of nearly all morphologic subtypes: potential prognostic implications. Blood 2000; 95 (6): 1942.
43. Dombret H et al. International phase 3 study of azacitidine vs conventionalcare regimens in older patients with newly diagnosed AML with >30% blasts. Blood 2015; 126 (3): 291–9.
44. Fenaux P et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: arandomised, open-label, phase III study. Lancet Oncol 2009; 10 (3): 223–32.
45. Phillips CL et al. Low dose decitabine in very high risk relapsed or refractory acute myeloid leukaemia in children and young adults. Br J Haematol 2013; 161 (3): 406–10.
46. Gore L et al. A multicenter, randomized study of decitabine as epigenetic priming with induction chemotherapy in children with AML. Clin Epigenet 2017; 9: 108.
47. Sun W et al. A phase 1 study of azacitidine combined with chemotherapy in childhood leukemia: a report from TACL consortium. Blood 2018; 131 (10): 1145–8.
48. Platzbecker U et al. Azacitidine for treatment of imminent relapse in MDS or AML patients after allogeneic HSCT: results of the RELAZA trial. Leukemia 2011; 26 (3): 381–9.
49. Stein EM, Tallman MS. Emerging therapeutic drugs for AML. Blood 2016; 127 (1): 71–8.
50. Stein EM et al. Enasidenib in mutant IDH2relapsed or refractory acute myeloid leukemia. Blood 2017; 130 (6): 722–31.
51. Andersson AK et al. IDH1 and IDH2 mutations in pediatric acute leukemia. Leukemia 2011; 25 (10): 1570–7.
52. Papaemmanuil E et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. New Engl J Med 2016; 374 (23): 2209–21.
53. Chan SM et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nature Med 2015; 21 (2): 178–84.
54. Qi J et al. HDAC8 Inhibition Specifically Targets Inv (16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell 2015; 17 (5): 597–610.
55. Garcia-Manero G et al. Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome. J Clin Oncol 2012; 30 (18): 2204–10.
56. Wang J et al. Inhibitors of Histone Deacetylase Relieve ETO-mediated Repression and Induce Differentiation of AML1-ETO Leukemia Cells. Cancer Res 1999; 59 (12): 2766.
57. Kuendgen A et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acutemyeloid leukemia. Cancer 2006; 106 (1): 112–9.
58. Gelmetti V et al. Aberrant Recruitment of the Nuclear Receptor Corepressor-Histone Deacetylase Complex by the Acute Myeloid Leukemia Fusion Partner ETO. Mol Cell Biol 1998; 18 (12): 7185–91.
59. Byrd JC. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100 (13): 4325–36.
60. Rubnitz JE et al. Characteristics and outcome of t (8;21)-positive childhood acute myeloid leukemia: a single institution’s experience. Leukemia 2002; 16 (10): 2072–7.
61. Balgobind BV et al. The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia. Leukemia 2011; 25 (8): 1239–48.
62. Karol SE et al. Prognostic factors in children with acute myeloid leukaemia and excellent response to remission induction therapy. Br J Haematol 2014; 168 (1): 94–101.
63. Shukla N et al. Final Report of Phase 1 Study of the DOT1L Inhibitor, Pinometostat (EPZ-5676), in Children with Relapsed or Refractory MLL-r Acute Leukemia. Blood 2016; 128 (22): 2780.
64. Liu W et al. DOT1L Inhibition Sensitizes MLL-Rearranged AML to Chemotherapy. PLoS One 2014; 9 (5): e98270–11.
Авторы
Г.З. Серегин1, А.В. Лифшиц2, Г.А. Алескерова1, Т.Т. Валиев*1
1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия;
2 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
*timurvaliev@mail.ru
1 Blokhin National Medical Research Center of Oncology, Moscow, Russia;
2 Pirogov Russian National Research Medical University, Moscow, Russia
*timurvaliev@mail.ru
1 ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина» Минздрава России, Москва, Россия;
2 ФГАОУ ВО «Российский национальный исследовательский медицинский университет им. Н.И. Пирогова» Минздрава России, Москва, Россия
*timurvaliev@mail.ru
________________________________________________
1 Blokhin National Medical Research Center of Oncology, Moscow, Russia;
2 Pirogov Russian National Research Medical University, Moscow, Russia
*timurvaliev@mail.ru
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