bloodjourГематология и трансфузиологияRussian journal of hematology and transfusiology0234-57302411-3042ООО Издательский дом «Практика»10.18821/0234-5730-2016-61-1-10-16bloodjour-7Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESЭффективность индукционной терапии у первичных больных множественной миеломой в зависимости от уровня экспрессии гена c-MYC в дебюте заболеванияEfficiency of induction therapy in primary patients with multiple myeloma depends on c-MYC gene expression at the debut of diseaseНарейкоМ. В.NareikoM. V.

Нарейко Мария Вячеславовна - врач-гематолог, аспирант научно-клинического отделения высокодозной химиотерапии парапротеинемических гемобластозов

125167, г. Москва

Nareyko Mariya V., MD, hematologist, post graduate of Clinical Research Department of High-Dose Chemotherapy Hemoblastosis, Depression of Hematopoiesis and Bone Marrow Transplantation

Moscow, 125167

nareyko@yandex.ruМенделееваЛ. П.MendeleevaL. P.

125167, г. Москва

Moscow, 125167

СуринВ. Л.SurinV. L.

125167, г. Москва

Moscow, 125167

ДемидоваЕ. Ю.DemidovaE. Yu.

125167, г. Москва

Moscow, 125167

ПокровскаяО. С.PokrovskayaO. S.

125167, г. Москва

Moscow, 125167

https://orcid.org/0000-0001-6201-6276КузьминаЛ. А.KuzminaL. A.

125167, г. Москва

Moscow, 125167

ГрибановаЕ. О.GribanovaE. O.

125167, г. Москва

Moscow, 125167

https://orcid.org/0000-0002-8490-6066ГальцеваИ. В.GaltsevaI. V.

Scopus Author ID: 6506926619

125167, г. Москва

Scopus Author ID: 6506926619

Moscow, 125167

УрноваЕ. С.UrnovaE. S.

125167, г. Москва

Moscow, 125167

https://orcid.org/0000-0001-9431-8316ДроковМ. Ю.DrokovM. Yu.

Scopus Author ID 48661939800

125167, г. Москва

Scopus Author ID 48661939800

Moscow, 125167

ФирсоваМ. В.FirsovaM. V.

125167, г. Москва

Moscow, 125167

СоловьевМ. В.SolovyovM. V.

125167, г. Москва

Moscow, 125167

МакунинаЭ. А.MakuninaE. A.

125167, г. Москва

Moscow, 125167

https://orcid.org/0000-0001-6177-3566ПаровичниковаЕ. Н.ParovichnikovaE. N.

125167, г. Москва

Moscow, 125167

https://orcid.org/0000-0003-2935-4040СавченкоВ. Г.SavchenkoV. G.

125167, г. Москва

Moscow, 125167

ФГБУ «Гематологический научный центр» Минздрава РоссииРоссияNational Research Center for HematologyRussian Federation2016240220196111016Copyright © Нарейко М.В., Менделеева Л.П., Сурин В.Л., Демидова Е.Ю., Покровская О.С., Кузьмина Л.А., Грибанова Е.О., Гальцева И.В., Урнова Е.С., Дроков М.Ю., Фирсова М.В., Соловьев М.В., Макунина Э.А., Паровичникова Е.Н., Савченко В.Г., 20192019Нарейко М.В., Менделеева Л.П., Сурин В.Л., Демидова Е.Ю., Покровская О.С., Кузьмина Л.А., Грибанова Е.О., Гальцева И.В., Урнова Е.С., Дроков М.Ю., Фирсова М.В., Соловьев М.В., Макунина Э.А., Паровичникова Е.Н., Савченко В.Г.Nareiko M.V., Mendeleeva L.P., Surin V.L., Demidova E.Y., Pokrovskaya O.S., Kuzmina L.A., Gribanova E.O., Galtseva I.V., Urnova E.S., Drokov M.Y., Firsova M.V., Solovyov M.V., Makunina E.A., Parovichnikova E.N., Savchenko V.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.htjournal.ru/jour/article/view/7

Настоящая работа посвящена определению зависимости характера противоопухолевого ответа на индукционную терапию больных множественной миеломой (ММ) и/или моноклональной гаммапатией неуточненного генеза (МГНГ) от уровня экспрессии гена c-MYC на момент диагностики заболевания. Экспрессию c-MYC определяли в клетках костного мозга методом мультиплексной полимеразной цепной реакции в режиме реального времени (qRT-PCR). Среднее значение уровня экспрессии гена с-MYC в CD138+-клетках у больных ММ/МГНГ выше, чем у доноров (р = 0,011). Выявлена взаимосвязь между глубиной противоопухолевого ответа и уровнем экспрессии c-MYC в СD138+-клетках.

The relationship between the type of antitumor response to induction therapy in patients with multiple myeloma (MM) and/or monoclonal gammopathy of undetermined significance (MGUS) and the level of c-MYC gene expression at the moment of disease diagnosis is studied. The expression of c-MYC in bone marrow cells was evaluated by multiplex RT-PCR. The mean levels of c-MYC gene expression in CD138+ cells of patients with MM/MGOO are higher than in donors (p = 0.011). Relationship between the depth of antitumor response and level of C-myc expression in CD138+ cells is detected.

множественная миеломаген c-MYCCD138+-клеткиmultiple myelomac-MYC geneCD138+ cellsРабота выполнена при поддержке Российского фонда фундаментальных исследований (грант № 15-04-02568).The work was supported by Russian Foundation for Basic Research (grant No. 15-04-02568).ReferencesPaszekova H., Kryukov F., Kubiczkova L., Hajek R., Sevcikova S. High-Risk Multiple Myeloma: Different defnitions, different outcomes? Clin. Lymphoma Myeloma Leuk. 2014; 14(1): 24–30. doi:10.1016/j.clml.2013.09.004.Paszekova H., Kryukov F., Kubiczkova L., Hajek R., Sevcikova S. High-Risk Multiple Myeloma: Different defnitions, different outcomes? Clin. Lymphoma Myeloma Leuk. 2014; 14(1): 24–30. doi:10.1016/j.clml.2013.09.004.Bergsagel P.L., Chesi M.V. Molecular classifcation and risk stratifcation of myeloma. Hematol. Oncol. 2013; 31(Suppl.1): 38–41. doi: 10.1002/hon.2065.Bergsagel P.L., Chesi M.V. Molecular classifcation and risk stratifcation of myeloma. Hematol. Oncol. 2013; 31(Suppl.1): 38–41. doi: 10.1002/hon.2065.Morgan G.J., Walker B.A., Davies F.E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer. 2012; 12(12): 335–48. doi: 10.1038/nrc3257.Morgan G.J., Walker B.A., Davies F.E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer. 2012; 12(12): 335–48. doi: 10.1038/nrc3257.Lorbach R.B., His E.D., Dogan A., Fend F. Plasma cell myeloma and related neoplasms. Am. J. Clin. Pathol. 2011; 136(2): 168–82. doi: 10.1309/AJCPENJ68FFBRIYB.Lorbach R.B., His E.D., Dogan A., Fend F. Plasma cell myeloma and related neoplasms. Am. J. Clin. Pathol. 2011; 136(2): 168–82. doi: 10.1309/AJCPENJ68FFBRIYB.Van Wier S., Braggio E., Baker A., Ahmann G., Levy J., Carpten J.D., et al. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma. Hematologica. 2013; 98(10): 1586–92. doi: 10.3324/haematol.2012.081083.Van Wier S., Braggio E., Baker A., Ahmann G., Levy J., Carpten J.D., et al. Hypodiploid multiple myeloma is characterized by more aggressive molecular markers than non-hyperdiploid multiple myeloma. Hematologica. 2013; 98(10): 1586–92. doi: 10.3324/haematol.2012.081083.Диагностика и лечение множественной миеломы. Рекомендации Британского форума по множественной миеломе и Скандинавской исследовательской группы по множественной миеломе, 2005. Стандарты мировой медицины. 2006; 2: 24–56.Smith A., Wisloff F., Samson D.; UK Myeloma Forum; Nordic Myeloma Study Group; British Committee for Standards in Haematology. Guidelines on the diagnosis and management of multiple myeloma, 2005. Br. J. Haematol. 2006; 132(4): 410–51.Bhatia K.G., Cherney B.W., Huppi K., Magrath I.T., Cossman J., Sausville E., et al. A deletion linked to a poly (ADP-ribose) polymerase gene on chromosome 13q33-qter occurs frequently in the normal black population as well as in multiple tumor DNA. Cancer Res. 1990; 50(17): 5406–13.Bhatia K.G., Cherney B.W., Huppi K., Magrath I.T., Cossman J., Sausville E., et al. A deletion linked to a poly (ADP-ribose) polymerase gene on chromosome 13q33-qter occurs frequently in the normal black population as well as in multiple tumor DNA. Cancer Res. 1990; 50(17): 5406–13.Давыдов М.И., Аксель Е.М. Заболеваемость злокачественными новообразованиями населения России и стран СНГ в 2007 г. Вестник РОНЦ им. Н.Н. Блохина РАМН. 2009; 3: 52–90.Davidov M.I., Aksel E.M. The incidence of malignant neoplasms of the population of Russia and the CIS in 2007. Journal of N.N. Blokhin Russian Cancer Research Center RAMS (Vestnik RONC im. N.N. Blokhina). 2009; 20(3): 52–90. (in Russian)Gonzalez G., van der Burg M., Garcia-Sanz R., Fenton J.A., Langerak A.W., Gonzalez M., et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood. 2007; 110(9): 3112–21.Gonzalez G., van der Burg M., Garcia-Sanz R., Fenton J.A., Langerak A.W., Gonzalez M., et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood. 2007; 110(9): 3112–21.Bergsagel P.L., Kuehl W.M., Zhan F., Sawyer J., Barlogie B., Shaughnessy J.Jr.. CyclinD dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(1): 296–303.Bergsagel P.L., Kuehl W.M., Zhan F., Sawyer J., Barlogie B., Shaughnessy J.Jr.. CyclinD dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood. 2005; 106(1): 296–303.Lwin T., Zhao X., Cheng F., Zhang X., Huang A., Shah B., et al. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplifcation loop in non-Hodgkin B cell lymphomas. J. Clin. Invest. 2013; 123(11): 4612–26.Lwin T., Zhao X., Cheng F., Zhang X., Huang A., Shah B., et al. A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplifcation loop in non-Hodgkin B cell lymphomas. J. Clin. Invest. 2013; 123(11): 4612–26.Terunuma A., Pulturi N., Mishra P., Mathe E.A., Dorsey T.H., Yi M., et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 2014; 124(1): 398–12. doi: 10.1172/JCI71180.Terunuma A., Pulturi N., Mishra P., Mathe E.A., Dorsey T.H., Yi M., et al. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 2014; 124(1): 398–12. doi: 10.1172/JCI71180.Affer M., Chesi M., Chen W.D., Keats J.J., Demchenko Y.N., Tamizhmani K., et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014; 28(8): 1725–35. doi: 10.1038/leu.2014.70.Affer M., Chesi M., Chen W.D., Keats J.J., Demchenko Y.N., Tamizhmani K., et al. Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia. 2014; 28(8): 1725–35. doi: 10.1038/leu.2014.70.Delgado M.D., Leon J. Myc roles in hematopoiesis and leukemia. Gen. Cancer. 2010; 1(6): 605–16. doi: 10.1177/1947601910377495.Delgado M.D., Leon J. Myc roles in hematopoiesis and leukemia. Gen. Cancer. 2010; 1(6): 605–16. doi: 10.1177/1947601910377495.Janz S. Myc translocations in B cell and plasma cell neoplasms. DNA Repair. 2006; 5(9–10): 1213–24.Janz S. Myc translocations in B cell and plasma cell neoplasms. DNA Repair. 2006; 5(9–10): 1213–24.Muller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factor precedes activation of c-myc. Nature. 1984; 312(5996): 716–20.Muller R., Bravo R., Burckhardt J., Curran T. Induction of c-fos gene and protein by growth factor precedes activation of c-myc. Nature. 1984; 312(5996): 716–20.Кабилова Т.О., Черноловская Е.Л. Онкогены семейства myc как терапевтические мишени. Бюллетень сибирской медицины. 2008; (Прил. 3): 11–26.Kabilova Т.О., Chernogolovskaya E.L. Myc-family oncogenes as therapeutic targets. Bulletin of Siberian medicine (Bulleten sibirskoy meditsine). 2008; (Issue 3): 11–26. (in Russian)Grand C.L., Powell T.J., Nagle R.B., Bearss D.J., Tye D., Gleason-Guzman M., Hurley L.H. Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue. Proc. Nat. Acad. Sci. USA. 2004; 101(16): 6140–5.Grand C.L., Powell T.J., Nagle R.B., Bearss D.J., Tye D., Gleason-Guzman M., Hurley L.H. Mutations in the G-quadruplex silencer element and their relationship to c-MYC overexpression, NM23 repression, and therapeutic rescue. Proc. Nat. Acad. Sci. USA. 2004; 101(16): 6140–5.Taniguchi M., Fujiwara K., Nakai Y., Ozaki T., Koshikawa N., Toshio K. et al. Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer, a pyrrole–imidazole polyamide, which targets an E-box motif. FEBS Open Bio. 2014;13(4): 328–34. doi: 10.1016/j.fob.2014.03.004.Taniguchi M., Fujiwara K., Nakai Y., Ozaki T., Koshikawa N., Toshio K. et al. Inhibition of malignant phenotypes of human osteosarcoma cells by a gene silencer, a pyrrole–imidazole polyamide, which targets an E-box motif. FEBS Open Bio. 2014;13(4): 328–34. doi: 10.1016/j.fob.2014.03.004.Chng W.J., Huang G.F., Chung T.H., Ng S.B., Gonzalez-Paz N., Troska-Price T., et al. Clinical and biological implications of MYC activation: a common difference between MGUS and Newly diagnosed multiple myeloma. Leukemia. 2011; 25(6): 1026–35. doi: 10.1038/leu.2011.53.Chng W.J., Huang G.F., Chung T.H., Ng S.B., Gonzalez-Paz N., Troska-Price T., et al. Clinical and biological implications of MYC activation: a common difference between MGUS and Newly diagnosed multiple myeloma. Leukemia. 2011; 25(6): 1026–35. doi: 10.1038/leu.2011.53.Zhan F., Hardin J., Kordsmeier B., Bumm K., Zheng M., Tian E., et al. Global gene expression profling of multiple myeloma, monoclonal gammopathy of undetermined signifcance, and normal bone marrow plasma cell. Blood. 2002; 99(5): 1745–57.Zhan F., Hardin J., Kordsmeier B., Bumm K., Zheng M., Tian E., et al. Global gene expression profling of multiple myeloma, monoclonal gammopathy of undetermined signifcance, and normal bone marrow plasma cell. Blood. 2002; 99(5): 1745–57.Zhan F., Barlogie B., Arzoumanian V., Huang Y., Williams D.R., Hollmig K., et al. Gene expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007; 109(4): 1692–700.Zhan F., Barlogie B., Arzoumanian V., Huang Y., Williams D.R., Hollmig K., et al. Gene expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood. 2007; 109(4): 1692–700.Klein U., Tu Y., Stolovitzky G.A., Keller J.L., Haddad J.Jr., Miljkovic V., et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Nat. Acad. Sci. USA. 2003; 100(5): 2639–44.Klein U., Tu Y., Stolovitzky G.A., Keller J.L., Haddad J.Jr., Miljkovic V., et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Nat. Acad. Sci. USA. 2003; 100(5): 2639–44.Zhan F., Tian E., Bumm K., Smith R., Barlogie B., Shaughnessy J.Jr. Gene expression profling of human plasma cell differentiation and classifcation of multiple myeloma based on similarities to distinct stages of late-stage-B-cell development. Blood. 2003; 101(3): 1128–40.Zhan F., Tian E., Bumm K., Smith R., Barlogie B., Shaughnessy J.Jr. Gene expression profling of human plasma cell differentiation and classifcation of multiple myeloma based on similarities to distinct stages of late-stage-B-cell development. Blood. 2003; 101(3): 1128–40.Jain M., Arvanitis C., Chu K., Dewey W., Leonhardt E., Trinh M., et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002; 297(5578): 102–4.Jain M., Arvanitis C., Chu K., Dewey W., Leonhardt E., Trinh M., et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science. 2002; 297(5578): 102–4.Chesi M., Robbiani D. F., Sebag M., Chng W.J., Affer M., Tiedemann R., et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of postgerminal center malignancies. Cancer Cell. 2008; 13(2): 167–80. doi: 10.1016/j.ccr.2008.01.007.Chesi M., Robbiani D. F., Sebag M., Chng W.J., Affer M., Tiedemann R., et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of postgerminal center malignancies. Cancer Cell. 2008; 13(2): 167–80. doi: 10.1016/j.ccr.2008.01.007.Pourdehnad M., Truitt M.L., Siddiqi I.N., Ducker G.S., Shokat K.M., Ruggero D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Nat. Acad. Sci. USA. 2013; 110(2): 11988–93. doi: 10.1073/pnas.1310230110.Pourdehnad M., Truitt M.L., Siddiqi I.N., Ducker G.S., Shokat K.M., Ruggero D. Myc and mTOR converge on a common node in protein synthesis control that confers synthetic lethality in Myc-driven cancers. Proc. Nat. Acad. Sci. USA. 2013; 110(2): 11988–93. doi: 10.1073/pnas.1310230110.Vandesompele J., De Preter K., Pattyn F., Poppe B., Van Roy N., De Paepe A., et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7): 1–12.Vandesompele J., De Preter K., Pattyn F., Poppe B., Van Roy N., De Paepe A., et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002; 3(7): 1–12.Rajkumar V., Dimopoulos M.A., Palumbo A., Blade J., Merlini G., Mateos M.V., et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15(12): e538–48. doi: 10.1016/S1470-2045(14)70442-5.Rajkumar V., Dimopoulos M.A., Palumbo A., Blade J., Merlini G., Mateos M.V., et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15(12): e538–48. doi: 10.1016/S1470-2045(14)70442-5.Durie B.G., Salmon S.E. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975; 36(3): 842–54.Durie B.G., Salmon S.E. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 1975; 36(3): 842–54.Durie B.G., Harousseau J.L., Miguel J.S., Blade J., Barlogie B., Anderson K., et al. International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467–73.Durie B.G., Harousseau J.L., Miguel J.S., Blade J., Barlogie B., Anderson K., et al. International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467–73.Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction. Anal. Biochem. 1987; 162(1): 156–9.Chomczynski P., Sacchi N. The single-step method of RNA isolation by acid guanidinum thiocyanate-phenol-chloroform extraction. Anal. Biochem. 1987; 162(1): 156–9.Holien T., Vatsveen T.K., Hella H., Rampa C., Brede G., Groseth L.A., et al. Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC. Leukemia. 2012; 26(5): 1073–80. doi: 10.1038/leu.2011.263.Holien T., Vatsveen T.K., Hella H., Rampa C., Brede G., Groseth L.A., et al. Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC. Leukemia. 2012; 26(5): 1073–80. doi: 10.1038/leu.2011.263.

The authors declare that there are no conflicts of interest present.