Mitochondrial translocation of p210 BCR-ABL rewires downstream signaling by selectively suppressing ERK activation.

Chronic myeloid leukemia (CML) is a myeloproliferative disorder driven by the fusion protein p210 BCR-ABL. In addition to activating canonical cytosolic signaling pathways, p210 BCR-ABL has been shown to translocate to the mitochondria upon mitochondrial damage through the interaction between its pleckstrin homology domain and cardiolipin, a mitochondria-specific phospholipid. We recently demonstrated that a fraction of p210 BCR-ABL localizes to the mitochondria in CML cells and promotes cell survival through mitochondria-associated signaling. However, whether mitochondria translocation of p210 BCR-ABL affects the major downstream signaling pathways activated by p210 BCR-ABL remains unclear. Here, we investigated the effects of mitochondrial translocation of p210-BCR-ABL on the JAK2/STAT5-, PI3K/AKT-, and RAS/MAPK-pathways using HEK293T cells expressing p210 BCR-ABL. Carbonyl cyanide m-chlorophenylhydrazone (CCCP), which induces mitochondrial damage and subsequent mitochondrial translocation of p210 BCR-ABL, markedly reduced ERK activation, whereas STAT5 and AKT activation were largely unaffected. Consistently, phosphorylation of SHC1, an adaptor protein directly phosphorylated by p210 BCR-ABL and required to ERK activation, was also suppressed by CCCP treatment. In contrast, CCCP did not affect EGF-induced ERK activation, indicating that the observed effect was specific for p210 BCR-ABL signaling. Moreover, N-acetylcysteine inhibited CCCP-induced reactive oxygen species production, prevented mitochondrial translocation of p210 BCR-ABL, and fully restored ERK-activation. These findings suggest that intercellular relocation of p210 BCR-ABL dynamically rewires downstream signaling networks, potentially optimizing the signaling balance required for CML cell survival and proliferation.