Characteristics ofBCR-ABLkinase domain mutations in chronic myeloid leukemia from India: not just missense mutations but insertions and deletions are also associated with TKI resistance

Abstract

We document the characteristics of BCR-ABL kinase domain mutations (KDM) in the largest study from India comprising of 385 patients and demonstrate that more than half (51.9%) of these patients have detectable abnormalities in the KD both in adult and in pediatric chronic myelogenous leukemia (CML). These comprise singly occurring missense mutations (25.5%), polyclonal/compound point mutations (4.9%), and insertions/deletions (29.6%). Missense mutations were most commonly seen in the imatinib-binding region followed by the P-loop. The commonest mutation in our dataset was T315I. Other common missense mutations were Y253H, M244V, and F317L. A high prevalence of BCR-ABL exon7 deletion (p.R362fs*) was also seen (25.5% of the entire cohort), whereas the 35bpintron-derived insertion/truncation mutation detected in 12 patients. In the pediatric age group, 58.8% of patients harbored missense mutations, polyclonal/compound mutations as well as insertions and deletions. We detected 11 novel mutations (seven missense mutations and four insertions/deletions).

Utilization of Next-Generation Deep Sequencing to Analyze BCR-ABL1 Kinase Domain Mutation for Imatinib-Resistant Chronic Myeloid Leukemia Patients in Vietnam

“…Our data again demonstrated that the incidence of mutation varies depending on the different populations. Most of cases with imatinib resistance in our study were in chronic phase, which is in line with previous observations [8,11,20]. Of those, 122 cases (86.5%) at chronic phase, 7 cases (5%) at accelerated phase and 12 cases (8.5%) at blast phase.…”

“…As the national diagnostic and treatment center for CML, we aimed to utilize NGS system (MiSeq sequencer, Illumina, USA) to investigate the occurrence and ratio of kinase domain mutations for a group of our CML patients in Vietnam. The results could add some more information to previous serial studies of kinase domain mutation of CML [8,11].…”

“…These include drug intolerance, enhance of BCR-ABL1 transcription level and most importantly, BCR-ABL1 kinase domain mutation [5]. A large number of mutations (mainly nucleotide substitution) have been observed, by Soverini and later by other groups, within approximately 600 base pairs of the kinase domain [9][10][11][12]. However, these mutations are showing different resistant properties to TKIs.…”

BCR‐ABL exon 7 deletion and novel point mutation in patient with chronic myelogenous leukemia and TKI resistance

“…In 2016, a group of Indian researchers6 conducted a large screening study (385 resistant patients) that revealed a statistically significant relationship between deletion and TKI resistance. Our screening study showed that the deletion is detected approximately equally in sensitive and TKI‐resistant patients (47% and 53%, respectively); this fact is consistent with the alternative splicing theory.…”

Tyrosine Kinase Inhibitor Resistance in Patients with Chronic Myeloid Leukemia: A 10-Year Study of BCR-ABL Gene Mutation Profile in Russia (2006-2016)

“…Согласно исследованиям, проведенным в раз-личных странах, спектр мутаций, частота обнаружения и доля ассоциированной с мутациями устойчивости оказываются примерно одинаковыми [4][5][6][7][8]. Наиболее часто встречающимися мутациями гена BCR-ABL (суммарно 85 %), связанными с резистентностью к иматинибу, являются семь: M244V, G250E, Y253F/H, E255K/V, T315I, M351T и F359V.…”