Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies
Elisa ten Hacken, Rebecca Valentin, Fara Faye D. Regis, Jing Sun, Shanye Yin, Lillian Werner, Jing Deng, Michaela Gruber, Jessica Wong, Mei Zheng, Amy L. Gill, Michael Seiler, Peter Smith, Michael Thomas, Silvia Buonamici, Emanuela M. Ghia, Ekaterina Kim, Laura Z. Rassenti, Jan A. Burger, Thomas J. Kipps, Matthew L. Meyerson, Pavan Bachireddy, Lili Wang, Robin Reed, Donna Neuberg, Ruben D. Carrasco, Angela N. Brooks, Anthony Letai, Matthew S. Davids, Catherine J. Wu
Elisa ten Hacken, Rebecca Valentin, Fara Faye D. Regis, Jing Sun, Shanye Yin, Lillian Werner, Jing Deng, Michaela Gruber, Jessica Wong, Mei Zheng, Amy L. Gill, Michael Seiler, Peter Smith, Michael Thomas, Silvia Buonamici, Emanuela M. Ghia, Ekaterina Kim, Laura Z. Rassenti, Jan A. Burger, Thomas J. Kipps, Matthew L. Meyerson, Pavan Bachireddy, Lili Wang, Robin Reed, Donna Neuberg, Ruben D. Carrasco, Angela N. Brooks, Anthony Letai, Matthew S. Davids, Catherine J. Wu
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Research Article Hematology Therapeutics

Splicing modulation sensitizes chronic lymphocytic leukemia cells to venetoclax by remodeling mitochondrial apoptotic dependencies

Abstract

The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1–based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.

Authors

Elisa ten Hacken, Rebecca Valentin, Fara Faye D. Regis, Jing Sun, Shanye Yin, Lillian Werner, Jing Deng, Michaela Gruber, Jessica Wong, Mei Zheng, Amy L. Gill, Michael Seiler, Peter Smith, Michael Thomas, Silvia Buonamici, Emanuela M. Ghia, Ekaterina Kim, Laura Z. Rassenti, Jan A. Burger, Thomas J. Kipps, Matthew L. Meyerson, Pavan Bachireddy, Lili Wang, Robin Reed, Donna Neuberg, Ruben D. Carrasco, Angela N. Brooks, Anthony Letai, Matthew S. Davids, Catherine J. Wu

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Figure 2

Splicing modulation by E7107 treatment broadly affects the CLL transcriptome.

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Splicing modulation by E7107 treatment broadly affects the CLL transcrip...
(A) Frequency of ΔPSI for significant splice changes from the RNA-Seq data of 11 CLL samples after 8 hours of treatment with 5 nM E7107 compared with DMSO-treated controls and volcano plot of ΔPSI versus negative logarithmic P values (–log10P) of all splicing changes. Pink and black dashed lines indicate thresholds of |ΔPSI| of 10% and FDR of 10% (i.e., –log10P = 1) for significant splice changes. Orange dots indicate significant intron retention events; light blue dots indicate significant cassette exon events; gray dots indicate all other categories of splice events. A similar analysis of CLL samples based on SF3B1 mutation status is provided in Supplemental Figure 2, A and B. (B) Proportion of events within intron retention (orange), cassette exon (blue), and all other splicing categories (gray), and numbers of significantly (FDR < 0.10 and |ΔPSI| > 10%) modulated events by E7107 within all the 11 CLL samples or within samples divided based on SF3B1 mutation status (6 SF3B1wt, 5 SF3B1mut). (C) Panther algorithm pathway enrichment analysis of the 1,000 most significant intron retention and the 1,000 most significant cassette exon events and the 1,904 events with |ΔPSI| > 90 after E7107 treatment as compared with DMSO control. Significant P values are indicated in the figure. The gray area shaded highlights pathways also enriched in Figure 1E. A similar analysis with a maximal stringency of |ΔPSI| = 100 for the third category is displayed in Supplemental Figure 2C. (D) Schematic representation of the BCL2 family members, colored based on the number of splicing aberrations induced by E7107 treatment (0, white; 10, dark green). Gene names are indicated in italics. When gene names differ from protein products, the respective protein name is indicated in parenthesis. (E) Linear regression of number of predicted protein-coding isoforms of BCL2 family members targeted by E7107 (y axis) and the number of splicing aberrancies induced by E7107 treatment (x axis). Spearman correlation R and P values are indicated in the figure.