A thirty-five nucleotides BCR-ABL1 insertion mutation of controversial significance confers resistance to imatinib in a patient with chronic myeloid leukemia (CML)

Marcé, Sílvia; Cortés, Montserrat; Zamora, Lurdes; Cabezón, Marta; Grau, Javier; Millá, Fuensanta; Feliú, Evarist

doi:10.1016/j.yexmp.2015.04.007

Cited by 10 publications

(6 citation statements)

References 12 publications

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“…RNA concentration was quantified, and 1 μg of total RNA was reverse transcribed to cDNA using SuperScript IV or MMLV Reverse Transcriptase with random hexamers/primers according to the manufacturer’s protocol (Invitrogen; Thermo Fisher Scientific, Inc, Waltham, MA, USA). BCR-ABL1 was amplified using PCR primers as previously described [ 17 ] using 3 μL of cDNA. PCR products were transferred to a QIAxcel (QIAGEN Inc, Hilden, Germany) to identify the type of transcript expressed depending on its size.…”

Section: Methodsmentioning

confidence: 99%

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

Marcé

Xicoy

García

et al. 2021

JCM

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The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine–kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate.

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Section: Methodsmentioning

confidence: 99%

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

Marcé

Xicoy

García

et al. 2021

JCM

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“…In addition to point mutations, some studies have reported resistance acquisition by abnormal splicing of BCR-ABL1 . These rare splicing mutations are associated with nucleotides insertion, namely the retention of 35 intronic nucleotides on exon 8 to 9 of ABL1 [ 44 , 45 ]. Furthermore, some mutations that confer resistance to Asciminib have been identified ( Table 1 ), and available preclinical and clinical studies have suggested that mutations in and around the myristylation pocket may also confer resistance to this TKI [ 32 , 37 , 46 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

102

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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“…Recently, alternative splicing variants such as an exon 7 deletion, insertion of 35 intronic nucleotides at the junction of exon 8/9, and an exon 6 frameshift; i.e. a CAGG transnucleotide insertion at the junction of exon 5/6, have been proposed as mechanisms of TKI resistance [3,4], although the clinical significance of these mutations in the effectiveness of TKIs remains controversial [2,3,[5][6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

The clinical outcomes of chronic myeloid leukemia patients harboring alternatively spliced BCR-ABL variants

et al. 2018

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Objectives and importance: Tyrosine kinase inhibitors (TKIs) are indispensable for the treatment of chronic myeloid leukemia (CML). However, alternative splicing variants have been recently proposed as mechanisms of TKI resistance, although the clinical significance of these mutations remains controversial. We here present the long-term clinical courses of three CML patients harboring such unique mutations and try to assess their clinical significances. Moreover, the exon 6 frameshift presented here has been rarely reported, which may provide important information on this rare mutation. Clinical presentation: We report three cases of CML harboring an exon 7 deletion, insertion of 35 intronic nucleotides and an exon 6 frameshift, respectively. Remarkably, all patients obtained better than molecular response following administration of TKIs. Discussion and conclusion: Three CML cases highlighted an association between such splicing variants and clinical outcomes. The premature termination in the kinase domain due to these mutations likely causes conformational changes and inhibits TKI binding, but it also results in abrogating kinase activities of CML cells. Thus, the above-mentioned mutants might less affect outcomes of treatment. Noteworthy, clinically available International Scale RT-PCR system cannot distinguish kinase-active mutants from kinase-inactive mutants, which may possibly influence upon interpretation of the treatment efficacy. Clonal quantification on respective mutants could more precisely evaluate CML status in these patients. Therefore, one should realize these important splicing variants and accumulate further experiences.

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A thirty-five nucleotides BCR-ABL1 insertion mutation of controversial significance confers resistance to imatinib in a patient with chronic myeloid leukemia (CML)

Cited by 10 publications

References 12 publications

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

The clinical outcomes of chronic myeloid leukemia patients harboring alternatively spliced BCR-ABL variants

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