BCR-ABL1 compound mutations in tyrosine kinase inhibitor–resistant CML: frequency and clonal relationships

Khorashad, Jamshid S.; Kelley, Todd W.; Szankasi, Philippe; Mason, Clinton C.; Soverini, Simona; Adrian, Lauren T.; Eide, Christopher A.; Zabriskie, Matthew S.; Lange, Thoralf; Estrada, Johanna; Pomicter, Anthony D.; Eiring, Anna M.; Kraft, Ira L.; Anderson, David J.; Gu, Zhimin; Alikian, Mary; Reid, Alistair; Foroni, Letizia; Marín, David; Druker, Brian J.; O’Hare, Thomas; Deininger, Michael W.

doi:10.1182/blood-2012-05-431379

Cited by 185 publications

(178 citation statements)

References 38 publications

Supporting

Mentioning

174

Contrasting

Unclassified

Order By: Relevance

“…Our work demonstrates that most patients failing imatinib therapy carry BCR-ABL1 mutations and that polymutants (22,23) are readily detected not only after sequential therapy but immediately after failure of imatinib therapy. We also mapped mutations to a hotspot region (residues 295-312) within the BCR-ABL1 kinase domain, which were associated with high resistance and poor clinical outcomes.…”

Section: Discussionmentioning

confidence: 91%

“…Most patients exhibiting imatinib resistance receive a second-generation TKI, such as nilotinib or dasatinib (17,18), which inhibit most clinically relevant BCR-ABL1 mutations, except for T315I (19,20). Sequential TKI therapy has been associated with the acquisition of more than one mutation in the same BCR-ABL1 protein (i.e., compound mutant or polymutant) (21)(22)(23). In transformation assays, the accumulation of more than one mutation within the same allele has been associated with increased oncogenic potential compared with each individual mutation (21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Gibbons

Pricl

Posocco

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The acquisition of mutations within the BCR-ABL1 kinase domain is frequently associated with tyrosine kinase inhibitor (TKI) failure in chronic myeloid leukemia. Sensitive sequencing techniques have revealed a high prevalence of compound BCR-ABL1 mutations (polymutants) in patients failing TKI therapy. To investigate the molecular consequences of such complex mutant proteins with regards to TKI resistance, we determined by cloning techniques the presence of polymutants in a cohort of chronic-phase patients receiving imatinib followed by dasatinib therapy. The analysis revealed a high frequency of polymutant BCR-ABL1 alleles even after failure of frontline imatinib, and also the progressive exhaustion of the pool of unmutated BCR-ABL1 alleles over the course of sequential TKI therapy. Molecular dynamics analyses of the most frequent polymutants in complex with TKIs revealed the basis of TKI resistance. Modeling of BCR-ABL1 in complex with the potent pan-BCR-ABL1 TKI ponatinib highlighted potentially effective therapeutic strategies for patients carrying these recalcitrant and complex BCR-ABL1 mutant proteins while unveiling unique mechanisms of escape to ponatinib therapy. compound mutation | ponatinib resistance

show abstract

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 99%

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Gibbons

Pricl

Posocco

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…2,11 These mutational constellations included combinations of T315I with the P-loop mutations G250E and E255V as well as T315I/F359V, which arise during treatment with ponatinib, as has been described earlier.…”

mentioning

confidence: 99%

BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

et al. 2017

View full text Add to dashboard Cite

“…A366V mutations (substitution) at the C-loop have also been described in a prior study (27) and confirmed by the Catalogue of Somatic Mutations in Cancer database (http://cancer.sanger.ac.uk/cosmic). According to localization, these mutations may be associated with drug resistance and could affect the binding mechanisms, but further analysis is required for confirmation.…”

Section: Discussionmentioning

confidence: 99%

Molecular screening and the clinical impacts of BCR‑ABL KD mutations in patients with imatinib‑resistant chronic myeloid leukemia

et al. 2017

View full text Add to dashboard Cite

Abstract. The present study aimed to detect the frequency of kinase domain (KD) mutations in order to evaluate their clinical significance and functional importance in 45 patients with chronic myeloid leukemia (CML) who were resistant to imatinib therapy. Sanger sequencing was used (45 patients), along with allele-specific oligonucleotide polymerase chain reaction (ASO-PCR; 3 patients), for the screening of mutations. BCR/ABL KD was amplified by nested PCR and sequencing was performed. Secondly, ASO-PCR was performed to confirm the results of the sequence analysis for E255K mutations. Mutations were detected in 11/45 patients (24.44%) via Sanger sequencing. D241G (4.4%), C369C (4.4%), K285N (2.2%), A380T (2.2%) and A366V (2.2%) mutations were detected. E255K (8.8%) was detected by ASO-PCR and Sanger sequencing. Mutations are a primary reason for suboptimal responses, loss of response and resistance to imatinib. In particular, the E255K mutation, which is characterized by resistance to imatinib and nilotinib, was detected in four patients. Analyzing the mutations and monitoring patients with CML may improve their prognosis and survival rate. ASO-PCR assays will be beneficial for the routine monitoring of mutations.

show abstract

BCR-ABL1 compound mutations in tyrosine kinase inhibitor–resistant CML: frequency and clonal relationships

Abstract: Key Points• For CML patients on TKI therapy, 70% of double mutations in the BCR-ABL1 kinase domain detected by direct sequencing are compound mutations.• Sequential, branching, and parallel routes to compound mutations were observed, suggesting complex patterns of emergence.

Cited by 185 publications

References 38 publications

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy

BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib

Molecular screening and the clinical impacts of BCR‑ABL KD mutations in patients with imatinib‑resistant chronic myeloid leukemia

Contact Info

Product

Resources

About