Proteogenomic analysis reveals cytoplasmic sequestration of RUNX1 by the acute myeloid leukemia–initiating CBFB::MYH11 oncofusion protein

Cytoplasmic transcription factor sequestration drives the pathogenesis of a rearranged leukemia

“…In an elegant study from Tim Ley’s laboratory published recently in the JCI , Day et al ( 2 ) defined another mechanism by which translocations can cause cancer, demonstrating that the CBFB::MYH1 oncofusion protein chimera drives oncogenesis by sequestering the transcription factor Runx1 in the cytoplasm.…”

“…For CBFB::MYH11 AML, however, the mechanisms driving pathogenesis were previously unclear. To address this, Day et al ( 2 ) fused the TurboID promiscuous biotin ligase ( 4 ) to oncogenes in a proximity-based labeling strategy to identify protein factors interacting with protein complexes associated with the CBFB::MYH11 oncofusion protein.…”

“…This approach revealed numerous cytoplasmic proteins in the CBFB::MYH11-TurboID interactome, indicating that cytoplasmic CBFB::MYH11 retention that may occur due to interaction of MYH11 with myosin and related cytoplasmic proteins. Using molecular, biochemical, and cell biology methods, Day et al ( 2 ) demonstrated that cytoplasmic CBFB::MYH11 retention in the cytoplasm resulted in sequestration of RUNX1 in the cytoplasm in a form of aggregates. RUNX1 aggregation due to CBFB::MYH11 retention in the cytosol was confirmed in primary human AML cells, suggesting that this is the actual mechanism of the disease in humans.…”

“…It was recently reported that truncated mutant forms of MLL4, which is found in a large number of cancers and developmental disorders such as Kabuki syndrome, relocalize to the cytoplasm in animal models of cancer and samples from patients with bladder cancer ( 6 ). The elegant report of the cytoplasmic retention of the CBFB::MYH11 chimera and concomitant sequestration of the RUNX transcription factor in the JCI provides a mechanism by which oncofusion genes drive the pathogenesis of hematological malignancies, informing both prognosis and therapeutic development ( 2 ).…”