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To elucidate dynamic changes in native  BCR‐ABL  and alternatively spliced tyrosine kinase inhibitor (TKI)‐resistant but function‐dead  BCR‐ABL Ins35bp   variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such  BCR‐ABL  variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing  BCR ‐ ABL Ins35bp  , accounting for 0.8% of the total IS  BCR ‐ ABL , corresponding to actual  BCR ‐ ABL Ins35bp   value of 1.1539% IS. TKI rapidly decreased native  BCR ‐ ABL  but not  BCR ‐ ABL Ins35bp  , leading to the initial increase in the proportion of  BCR ‐ ABL Ins35bp  . Thereafter, both native  BCR ‐ ABL  and  BCR ‐ ABL Ins35bp   gradually decreased in the course of TKI treatment, whereas small populations positive for TKI‐resistant  BCR ‐ ABL Ins35bp   continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native  BCR ‐ ABL  +  clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function‐dead  BCR ‐ ABL Ins35bp  , suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis‐splicing  BCR ‐ ABL Ins35bp  , occurring at the particular pseudo‐splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional  BCR ‐ ABL  extracting  BCR ‐ ABL Ins35bp   would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention.

Tyrosine kinase inhibitors induce alternative spliced BCR‐ABL Ins35bp variant via inhibition of RNA polymerase II on genomic BCR‐ABL