Fig. 1: Deletion of SH3, SH2, SH3/SH2 and ABL1 exon2 (resulting in the BCR::ABL1/b3a3 isoform) in BCR::ABL1 confers asciminib resistance. | Leukemia

Fig. 1: Deletion of SH3, SH2, SH3/SH2 and ABL1 exon2 (resulting in the BCR::ABL1/b3a3 isoform) in BCR::ABL1 confers asciminib resistance.

From: Absence of ABL1 exon 2-encoded SH3 residues in BCR::ABL1 destabilizes the autoinhibited kinase conformation and confers resistance to asciminib

Fig. 1

A (Left) Schematic depiction of ABL1-SH3 (gold), SH2 (maroon) and SH1 (kinase; blue) domains in an active, disassembled conformation and in an assembled autoinhibited conformation upon binding of asciminib (red). (Right) Schematic depiction of sequences encoded by exon 2 [pink; (“b3a3”)] in the SH3 domain and hypothesized resultant disruption of autoinhibited conformation despite asciminib binding. B (Upper) Schematic representation of BCR::ABL1 deletions. Location of SH3 (“3”), SH2 (“2”) domains is depicted. (Lower) Proliferation assays of pools of Ba/F3 cells transformed to IL-3 independence by BCR::ABL1 isoforms in varying concentrations of TKIs for 48 h and assessed by CellTiter-Glo. Ba/F3 parental cells were grown in the presence of IL-3. Results were performed in technical and biological triplicate. Mean values and standard errors are depicted. Table provides calculated EC50 values. C Western immunoblot analysis of lysates of Ba/F3 cells transformed by BCR::ABL1 or BCR::ABL1/b3a3 and exposed to TKIs at the concentrations indicated for two hours. D Molecular response of a CML patient with BCR::ABL1/b2a3 while on treatment with imatinib and asciminib.

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