First- and second-generation tyrosine kinase inhibitors (TKIs) used for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have precise spectra of resistant BCR-ABL1 kinase domain (KD) mutations. Their sequential use may select for complex patterns resulting from the acquisition of multiple mutations either by the same or by distinct BCR-ABL1 alleles (compound mutants [CM] or polyclonal mutants [PM], respectively) [1, 2]. In silico molecular modeling [3] and in vitro drug sensitivity studies in cell lines [4, 5] have suggested that CMs might confer oncogenic properties and a degree of resistance substantially different (greater) than each individual mutation in separate clones would exhibit. In particular, when the IC50 of imatinib [3, 4], dasatinib [3, 4], nilotinib [4], bosutinib [4] and ponatinib [3,4,5] were assessed in BaF3 cells engineered to express a panel of CMs, the fold-increase over unmutated BCR-ABL1 led to hypothesize that several CMs would be challenging for all TKIs including ponatinib. The prevalence of CMs at baseline and at relapse has been investigated in 267 TKI-resistant chronic phase (CP)-CML patients enrolled in the Ponatinib Ph+ ALL and CML Evaluation (PACE) study [6]. Besides this, no further attempts have been made to compile a catalog of the most frequent CMs detectable in large series of Ph+ leukemia patients, nor to correlate in vitro predictions about TKI insensitivity with in vivo observations. We thus reviewed the results of routine BCR-ABL1 KD mutation screening performed by targeted next generation sequencing (NGS) over the past 4 years, in order to: (i) determine the prevalence and spectrum of CMs in a large series of patients; (ii) attempt a correlation between TKI resistance and the presence or acquisition of given CMs in vivo.

Sica, S., BCR-ABL1 compound mutants prevalence spectrum and correlation with tyrosine kinase inibitor resistance in a consecutive series of philadelphia chromosome-positive leukemia patients analyzed by NGS, <<LEUKEMIA>>, 2021; (7): 2102-2107 [http://hdl.handle.net/10807/203302]

BCR-ABL1 compound mutants prevalence spectrum and correlation with tyrosine kinase inibitor resistance in a consecutive series of philadelphia chromosome-positive leukemia patients analyzed by NGS

Sica, Simona
Secondo
Membro del Collaboration Group
2021

Abstract

First- and second-generation tyrosine kinase inhibitors (TKIs) used for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have precise spectra of resistant BCR-ABL1 kinase domain (KD) mutations. Their sequential use may select for complex patterns resulting from the acquisition of multiple mutations either by the same or by distinct BCR-ABL1 alleles (compound mutants [CM] or polyclonal mutants [PM], respectively) [1, 2]. In silico molecular modeling [3] and in vitro drug sensitivity studies in cell lines [4, 5] have suggested that CMs might confer oncogenic properties and a degree of resistance substantially different (greater) than each individual mutation in separate clones would exhibit. In particular, when the IC50 of imatinib [3, 4], dasatinib [3, 4], nilotinib [4], bosutinib [4] and ponatinib [3,4,5] were assessed in BaF3 cells engineered to express a panel of CMs, the fold-increase over unmutated BCR-ABL1 led to hypothesize that several CMs would be challenging for all TKIs including ponatinib. The prevalence of CMs at baseline and at relapse has been investigated in 267 TKI-resistant chronic phase (CP)-CML patients enrolled in the Ponatinib Ph+ ALL and CML Evaluation (PACE) study [6]. Besides this, no further attempts have been made to compile a catalog of the most frequent CMs detectable in large series of Ph+ leukemia patients, nor to correlate in vitro predictions about TKI insensitivity with in vivo observations. We thus reviewed the results of routine BCR-ABL1 KD mutation screening performed by targeted next generation sequencing (NGS) over the past 4 years, in order to: (i) determine the prevalence and spectrum of CMs in a large series of patients; (ii) attempt a correlation between TKI resistance and the presence or acquisition of given CMs in vivo.
Inglese
Sica, S., BCR-ABL1 compound mutants prevalence spectrum and correlation with tyrosine kinase inibitor resistance in a consecutive series of philadelphia chromosome-positive leukemia patients analyzed by NGS, <<LEUKEMIA>>, 2021; (7): 2102-2107 [http://hdl.handle.net/10807/203302]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10807/203302
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