TY - JOUR
T1 - Genetic alterations in the BCR-ABL1 fusion gene related to imatinib resistance in chronic myeloid leukemia
AU - Martínez-Castillo, Macario
AU - Gómez-Romero, Laura
AU - Tovar, Hugo
AU - Olarte-Carrillo, Irma
AU - García-Laguna, Anel
AU - Barranco-Lampón, Gilberto
AU - De la Cruz-Rosas, Adrián
AU - Martínez-Tovar, Adolfo
AU - Hernández-Zavala, Araceli
AU - Córdova, Emilio J.
N1 - Publisher Copyright:
© 2023 Elsevier Ltd
PY - 2023/8
Y1 - 2023/8
N2 - Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.
AB - Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.
KW - BCR-ABL1
KW - Chronic myeloid leukemia
KW - Imatinib
KW - Next-generation sequencing
KW - Point mutation
KW - Resistance
UR - http://www.scopus.com/inward/record.url?scp=85161072304&partnerID=8YFLogxK
U2 - 10.1016/j.leukres.2023.107325
DO - 10.1016/j.leukres.2023.107325
M3 - Artículo
C2 - 37302352
AN - SCOPUS:85161072304
SN - 0145-2126
VL - 131
JO - Leukemia Research
JF - Leukemia Research
M1 - 107325
ER -