[Tyrosine kinase inhibitors induce production of BCR-ABLIns35bp splicing variants via inhibition of RNA polymerase II on genomic BCR-ABL and cause unachieved deep molecular response and fluctuating minimal residual disease]

Junichiro Yuda

doi:10.11406/rinketsu.63.880

[Tyrosine kinase inhibitors induce production of BCR-ABL^Ins35bp splicing variants via inhibition of RNA polymerase II on genomic BCR-ABL and cause unachieved deep molecular response and fluctuating minimal residual disease]

Rinsho Ketsueki. 2022;63(8):880-892. doi: 10.11406/rinketsu.63.880.

[Article in Japanese]

Author

Junichiro Yuda¹

Affiliation

¹ Department of Hematology and Experimental Therapeutics, National Cancer Center Hospital East.

PMID: 36058859
DOI: 10.11406/rinketsu.63.880

Abstract

Deep sequence analysis for BCR-ABL revealed that native BCR-ABL decreased slowly after an exponential decrease within three months of tyrosine kinase inhibitor (TKI) treatment. BCR-ABL^Ins35bp was present at diagnosis and increased to account for 15-30% of total BCR-ABL when IS BCR-ABL was reduced to 1%. Native BCR-ABL and BCR-ABL^Ins35bp correspond to early relapse and fluctuating minimal residue disease, respectively, in the STOP-TKI trial. These findings highlight the clinical significance of quantifying BCR-ABL^Ins35bp. We discovered pseudosplice sites at both ends of 35 bp within ABL intron 8, and TKI off-target effect inhibited RNAPII S2P and reduced native BCR-ABL expression but induced BCR-ABL^Ins35bp mis-splicing.

Keywords: BCR-ABLIns35bp; Deep sequence; Minimal residual disease; RNA polymerase II.

MeSH terms

Fusion Proteins, bcr-abl*
Genomics
Humans
Neoplasm, Residual
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
RNA Polymerase II*

Substances

Protein Kinase Inhibitors
Fusion Proteins, bcr-abl
RNA Polymerase II