The partner gene modulates response to asciminib in ABL1-rearranged Acute Lymphoblastic Leukemia

ABL -rearranged ( ABL r) acute lymphoblastic leukemia (ALL) is associated with treatment failure and relapse and novel treatments are required. We investigated asciminib efficacy against NUP214::ABL1 ALL, the second most common ABL1 rearrangement associated with aggressive disease. Asciminib activity was established in three patient derived xenograft models of NUP214::ABL1 ALL with different ABL1 breakpoints (e31a2, e32a3, e34a3). In all models, treatment with asciminib reduced NUP214::ABL1 leukemic burden and increased survival outcomes compared with control mice. These results contrast with recent in vitro studies in the setting of BCR::ABL1 leukemia, where ABL1 exon 3 breakpoints (e13a3, e14a3) result in asciminib resistance due to incomplete SH3 domain. Conversely, in silico modeling of NUP214::ABL1 e32a3 predicted NUP214 exon 32 mimics the missing ABL1 exon 2, forming a chimeric SH3 domain that rescues asciminib sensitivity. This prediction was supported by viability assays of Ba/F3 cells expressing NUP214::ABL1 with exon 32 present and absent. Additional viability assays and structural modeling of NUP214::ABL1 Ba/F3 cells expressing various ABL1 deletions defined a region of the SH3 domain critical for asciminib efficacy and necessary for allosteric inhibition. Our findings establish asciminib as a potential treatment for NUP214::ABL1 ALL and reveal a critical role for the fusion partner gene. Asciminib efficacy in ABL r leukemia cannot be predicted by evaluating ABL1 exon 2 inclusion/exclusion in isolation. This is of clinical importance as first-line use of STAMP inhibitors such as asciminib becomes more common.