Detección de mutaciones en el dominio tirosina quinasa de BCR-ABL1 en pacientes colombianos con leucemia mieloide crónica LMC, resistentes al imatinib
DOI:
https://doi.org/10.35509/01239015.170Palabras clave:
Leucemia mieloide crónica, Inhibidor de tirosina quinasa, Mutaciones en el dominio tirosina quinasa, Resistencia a imatinib, BCR-ABL1Resumen
Introducción: Las mutaciones en el dominio BCR-ABL1, tirosina quinasa (TK) son mecanismos importantes de resistencia de los inhibidores de la tirosina quinasa (ITK) en pacientes con leucemia mieloide crónica (LMC).
Objetivo: Determinar el tipo y la frecuencia de las mutaciones en el dominio tirosina quinasa del gen BCR-ABL1, asociadas con falla en la respuesta al tratamiento con imatinib en pacientes con LMC y correlacionar el perfil de mutaciones con los hallazgos clínicos, demográficos, respuesta citogenética y respuesta molecular.
Materiales y métodos: Se realizó un estudio descriptivo de tipo prospectivo en pacientes con LMC en tratamiento con IMATINIB a quienes se les realizó cariotipo y análisis de mutaciones del dominio BCR-ABL1 mediante la técnica de PCR anidada.
Resultados: De los 23 pacientes estudiados en cuatro se encontraron mutaciones: dos presentaron la mutación E255K, uno presentó la mutación H396P y otro presentó doble mutación L387Ly T389P. Las mutaciones E255K que se ubican en la región P-loop y H396P en A-loop se asocian con mal pronóstico. La mutación T389P localizada en la región A-loop no está informada en algunas bases de datos.
Conclusiones: En este estudio encontramos cuatro mutaciones en el dominio tirosina quinasa (E255K, H396P, L387L y T389P) que podrían aportar información valiosa y guiar las decisiones de tratamiento. Es importante destacar que esta investigación de análisis mutacional del dominio BCR-ABL es la primera que se realiza en el país con la particularidad adicional de cubrir una población triétnica.
Biografía del autor/a
Gonzalo Vásquez Palacio Vásquez Palacio, Universidad de Antioquia
Unidad de Genética Médica, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
Gloria Cecilia Ramírez, Universidad de Antioquia
Unidad de Genética Médica, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
Carlos Enrique Muskus, Universidad de Antioquia
Programa de Estudio y Control de Enfermedades Tropicales, PECET, Facultad de Medicina, Universidad de Antioquia, Medellín,
Colombia
José Domingo Torres Torres, Hospital San Vicente de Paúl
Departamento de Medicina Interna, Facultad de Medicina, Universidad de Antioquia, Hospital San Vicente de Paúl, Medellín,Colombia
Carlos Alberto Aya, Universidad de Antioquia
Unidad de Genética Médica, Departamento de Pediatría, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia
Referencias bibliográficas
Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290-3.
https://doi.org/10.1038/243290a0
Shtivelman E, Lifshitz B, Gale RP, Canaani E. Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature. 1985;315:550-4.
https://doi.org/10.1038/315550a0
Lugo TG, Pendergast AM, Muller AJ, Witte ON. Tyrosine kinase activity and transformation potency of bcr-abl oncogene products. Science. 1990;247:1079-82.
https://doi.org/10.1126/science.2408149
Sloma I, Jiang X, Eaves AC, Eaves CJ. Insights into the stem cells of chronic myeloid leukemia. Leukemia. 2010;24:1823-33.
https://doi.org/10.1038/leu.2010.159
Quintás-Cardama A, Cortes J. Molecular biology of BCR-ABL1-positive chronic myeloid leukemia. Blood. 2009;113:1619-30.
https://doi.org/10.1182/blood-2008-03-144790
Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36:93-9.
https://doi.org/10.1016/0092-8674(84)90077-1
Usui N. Molecular targeted treatment - new treatment strategy for patients with chronic myeloid leukemia. Rinsho Byori. 2004;52:136-44.
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391-405.
https://doi.org/10.1182/blood-2016-03-643544
Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol. 2009;27:6041-51.
https://doi.org/10.1200/JCO.2009.25.0779
Deininger MW, Druker BJ. Specific Targeted Therapy of Chronic Myelogenous leukemia with imatinib. Pharmacol Rev. 2003;55:401-23.
https://doi.org/10.1124/pr.55.3.4
Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, Gattermann N, et al. Five-year follow-up of patients receiving imatinib for chronic myeloidleukemia. N Engl J Med. 2006;355:2408-17.
https://doi.org/10.1056/NEJMoa062867
Wu J, Meng F, Kong LY, Peng Z, Ying Y, Bornmann WG, et al. Association betweenimatinib-resistant BCR-ABL mutation-negative leukemia and persistent activation of LYN kinase. J Natl Cancer Inst. 2008;100:926-39.
https://doi.org/10.1093/jnci/djn188
Kantarjian HM, Shah NP, Cortes JE, Baccarani M, Agarwal MB, Undurraga MS, et al. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloidleukemia: 2-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2012;119: 1123-9.
https://doi.org/10.1182/blood-2011-08-376087
Larson RA, Hochhaus A, Hughes TP, Clark RE, Etienne G, Kim DW, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-yearfollow-up. Leukemia. 2012;26:2197-203.
https://doi.org/10.1038/leu.2012.134
Kantarjian H, Shah NP, Hochhaus A, Cortes J, Shah S, Ayala M, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-70.
https://doi.org/10.1056/NEJMoa1002315
Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, Lobo C, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-9.
https://doi.org/10.1056/NEJMoa0912614
Lussana F, Intermesoli T, Stefanoni P, Rambaldi A. Mechanisms of Resistance to Targeted Therapies in Chronic Myeloid Leukemia. In:. Handbook of Experimental Pharmacology. Berlin, Heidelberg: Springer; 2018.
https://doi.org/10.1007/164_2017_81
La Rosée P, Deininger MW. Resistance to imatinib: mutations and beyond. Semin Hematol. 2010;47:335-43.
https://doi.org/10.1053/j.seminhematol.2010.06.005
Hochhaus A. Chronic myelogenous leukemia (CML): resistance to tyrosinekinase inhibitors. Ann Oncol. 2006;17 Suppl. 10:x274-9.
https://doi.org/10.1093/annonc/mdl273
NCCN Clinical Practice Guidelines in Oncology. NCCN Chronic Myeloge-nous Leukemia Guidelines Vers 2. NCCN; 2017.
O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12:513-26.
https://doi.org/10.1038/nrc3317
Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res. 2009;15:7519-27.
https://doi.org/10.1158/1078-0432.CCR-09-1068
Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al., BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208-15.
https://doi.org/10.1182/blood-2010-12-326405
Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013;122:872-84.
https://doi.org/10.1182/blood-2013-05-501569
Corbin AS, La Rosée P, Stoffregen EP, Druker BJ, Deininger MW. Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib. Blood. 2003;101:4611-4.
https://doi.org/10.1182/blood-2002-12-3659
Grant H, Jiang X, Stebbing J, Foroni L, Craddock C, Griffiths M, et al. Analysis of BCR-ABL1 tyrosine kinase domain mutational spectra in primitive chronic myeloid leukemia cells suggests a unique mutator phenotype. Leukemia. 2010;24:1817-21.
https://doi.org/10.1038/leu.2010.179
Jabbour E, Kantarjian H, Jones D, Talpaz M, Bekele N, O'Brien S, et al. Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate. Leukemia. 2006;20:1767-73.
https://doi.org/10.1038/sj.leu.2404318
Jabbour, Elias. Jorge Cortes, and Hagop Kantarjian. ''Long-Term Outcomes in the Second-Line Treatment of Chronic Myeloid Leukemia: A Review of Tyrosine Kinase Inhibitors. In: ''. Cancer 117.5. 2011:897-906.
https://doi.org/10.1002/cncr.25656
Soverini S, Hochhaus A, Nicolini FE, Gruber F, Lange T, Saglio G, et al., BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European Leukemia Net. Blood. 2011;118:1208-15.
https://doi.org/10.1182/blood-2010-12-326405
Qin Y, Chen S, Jiang B, Jiang Q, Jiang H, Li J, et al. Characteristics of BCR-ABL kinase domain point mutations in Chinese imatinib resistant chronic myeloid leukemia patients. Ann Hematol. 2011;90:47-52.
https://doi.org/10.1007/s00277-010-1039-5
Hughes T, Saglio G, Branford S, Soverini S, Kim DW, Muller MC, et al. Impact ofbaseline BCR-ABL mutations on response to nilotinib in patients with chronicmyeloid leukemia in chronic phase. J Clin Oncol. 2009;27:4204-10.
https://doi.org/10.1200/JCO.2009.21.8230
Soverini S, Gnani A, Colarossi S, Castagnetti F, Abruzzese E, Paolini S, et al. Philadelphia-positive patients who already harbor imatinib-resistant Bcr-Ablkinase domain mutations have a higher likelihood of developing additionalmutations associated with resistance to second- or third-line tyrosine kinaseinhibitors. Blood. 2009;114:2168-71.
https://doi.org/10.1182/blood-2009-01-197186
Parker WT, Lawrence RM, Ho M, Irwin DL, Scott HS, Hughes TP, et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemiaafter imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol.2011;29:4250-9.
https://doi.org/10.1200/JCO.2011.35.0934
Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8:1018-29.
https://doi.org/10.1016/S1470-2045(07)70342-X
Alikian M, Gerrard G, Subramanian PG, Mudge K, Foskett P, Khorashad JS, et al. BCR - ABL1 kinase domain mutations: methodology and clinical evaluation. Am J Hematol. 2012;87:298-304.
https://doi.org/10.1002/ajh.22272
Baccarani M, Castagnetti F, Gugliotta G, Rosti G. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol. 2015;94 Suppl:S141-7.
https://doi.org/10.1007/s00277-015-2322-2
Branford S, Rudzki Z, Walsh S, Grigg A, Arthur C, Taylor K, et al. High frequency of point mutations clustered within the adenosine triphosphate-binding region of BCR/ABL in patients with chronic myeloid leukemia or Ph-positive acute lymphoblastic leukemia who develop imatinib (STI571) resistance. Blood. 2002;99:3472-5.
https://doi.org/10.1182/blood.V99.9.3472
Khorashad JS, Anand M, Marin D, Saunders S, Al-Jabary T, Iqbal A, et al. The presence of a BCR-ABL mutant allele in CML does not always explain clinical resistance to imatinib. Leukemia. 2006;20:658-63.
https://doi.org/10.1038/sj.leu.2404137
Mascarenhas CC, Cunha AF, Miranda EC, Zulli R, Silveira RA, Costa FF. New mutations detected by denaturing high performance liquid chromatography during screening of exon 6 bcr-abl mutations in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors. Leuk Lymphoma. 2009;50:1148-54.
https://doi.org/10.1080/10428190902930496
Machova KM, Lopotova T, Klamová H, Moravcová J. Highresolution melt curve analysis: Initial screening for mutations in BCR-ABL kinase domain. Leuk Res. 2008;32:1236-43.
https://doi.org/10.1016/j.leukres.2008.01.010
Soverini S. De Benedittis C, Polakova KM, Linhartova J. Castagnetti F. Next-generation sequencing for sensitive detection of BCR-ABL1 mutations relevant to tyrosine kinase inhibitor choice in imatinib-resistant patients. Oncotarget. 2016;7:21982-90.
https://doi.org/10.18632/oncotarget.8010
McGowan-Jordan J, Simons A, Schmid M. An International System for Human Cytogenomic Nomenclature. ISCN; 2016.
https://doi.org/10.1159/isbn.978-3-318-05979-3
Catalogue Of Somatic Mutations In Cancer. Disponible en: http://cancer.sanger.ac.uk/cosmic
Shundong Cang, Delong Liu. P-loop mutations and novel therapeutic approaches for imatinib failures in chronic myeloid leukemia. Journal of Hematology & Oncology. 2008;1:15.
https://doi.org/10.1186/1756-8722-1-15
Ernst T, La Rosée P, Müller MC, Hochhaus A. BCR-ABL mutations in chronic myeloid leukemia. Hematol Oncol Clin North Am. 2011;25:997-1008, v-vi.
https://doi.org/10.1016/j.hoc.2011.09.005
Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16:2190-6.
https://doi.org/10.1038/sj.leu.2402741
Lahaye T, Riehm B, Berger U, Paschka P, Müller MC, Kreil S, et al. Response and resistance in 300 patients with BCR-ABLpositive leukemias treated with imatinib in a single center: a 4.5-yearfollow-up. Cancer. 2005. 2005;103:1659-69.
https://doi.org/10.1002/cncr.20922
Soverini S, Colarossi S, Gnani A, Rosti G, Castagnetti F, Poerio A, et al. Contribution of ABL kinase domain mutations to imatinib resistance in different subsets of Philadelphia-positive patients: by the GIMEMA working party on chronic myeloid leukemia. Clin Cancer Res. 2006;12:7374-9.
https://doi.org/10.1158/1078-0432.CCR-06-1516
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor ofthe Abltyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2:561-6.
https://doi.org/10.1038/nm0596-561
Corbin AS, Buchdunger E, Pascal F, Druker BJ. Analysis of the structural basis of specificity of inhibition of the Abl kinase by STI571. J Biol Chem. 2002;277:32214-9.
https://doi.org/10.1074/jbc.M111525200
Ursan ID, Jiang R, Pickard EM, Lee TA, Ng D, Pickard AS. Emergence of BCR-ABL kinase domain mutations associated with newly diagnosed chronic myeloid leukemia: a meta-analysis of clinical trials of tyrosine kinase inhibitors. J Manag Care Spec Pharm. 2015;21:114-22.
https://doi.org/10.18553/jmcp.2015.21.2.114
Branford S, Melo JV, Hughes TP. Selecting optimal second-line tyrosine kinase inhibitor therapy for chronic myeloid leukemia patients after imatinib failure: does the BCR-ABL mutation status really matter? Blood. 2009;114:5426-35.
https://doi.org/10.1182/blood-2009-08-215939
O'Hare T, Eide CA, Deininger MW. Bcr-Abl kinase domain mutations, drug resistance, and the road to a cure for chronic myeloid leukemia. Blood. 2007;110:2242-9.
https://doi.org/10.1182/blood-2007-03-066936
Redaelli S, Piazza R, Rostagno R, Magistroni V, Perini P, Marega M, et al. Activity of bosutinib, dasatinib, and nilotinib against 18 imatinib-resistant BCR/ABL mutants. J Clin Oncol. 2009;27:469-71.
https://doi.org/10.1200/JCO.2008.19.8853
Soverini S, Martinelli G, Rosti G, Bassi S, Amabile M, Poerio A,et al. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA working party on chronic myeloid leukemia. J Clin Oncol. 2005;23:4100-9.
https://doi.org/10.1200/JCO.2005.05.531
Soverini S, Branford S, Nicolini FE, Talpaz M, Deininger MW, Martinelli G, et al. Implications of BCR-ABL1 kinase domain mediated resistance in chronic myeloid leukemia. Leuk Res. 2014;38:10-20.
Cómo citar
Descargas
Publicado
Número
Sección
Licencia
Todos los derechos reservados.
