Figure 2.
Mechanisms by which fusion genes promote kinase activation and cell survival and opportunities for therapeutic intervention. This figure shows two common gene rearrangements in ALL, BCR-ABL1 (left panel) and P2RY8-CRLF2 (right panel). The schematics depicting each fusion were produced using a program for visualization of gene rearrangements from RNA sequencing data (Clinker https://github.com/Oshlack/Clinker. Please note that the JBC is not responsible for the long-term archiving and maintenance of this site or any other third party hosted site.). The Clinker images show, from top to bottom, the coverage of reads mapped to each fusion, functional domains, and transcript variants. The breakpoint in each gene and associated fusion is also shown. The pathways show downstream kinases that are activated as a result of each fusion and consequently the impact on expression and/or degradation of mediators of cell survival. Therapeutic interventions at each point are shown in the red-shaded boxes. Constitutive activation of the ABL1 kinase, mediated by BCR-ABL1, promotes activation of the RAS/RAF/MEK/ERK pathway. Tyrosine kinase inhibitors can be used to either target ABL1 (imatinib, dasatinib, or ponatinib) directly or by MEK inhibitors. Phosphorylation of ERK, in turn, decreases BIM expression, blocks MCL-1 degradation, and increases BCL-2 expression. This prevents BAX/BAK activation. Pro-survival proteins BCL-2 and BCL-XL can be therapeutically targeted with BH3-mimetics (ABT-737, ABT-263, or ABT-199). The P2RY8-CRLF2 fusion cooperates with JAK2 mutations, the most common of which, p.R683G/R683S/R683T/R683K, is depicted to promote cell survival. Activated JAK2 can be directly inhibited with ruxolitinib. STAT5 promotes transcription and increased expression of BCL-XL, and perhaps BCL-2 and MCL-1 also. Treatment with BH3-mimetics may increase the capacity of these cells to undergo apoptosis in response to JAK2 inhibition.