Histone chaperone ASF1A accelerates chronic myeloid leukemia blast crisis by activating Notch signaling

The blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), which remains a major challenge in clinical management. However, the underlying molecular mechanism driving blastic transformation remains unclear. Here, we show that ASF1A, an essential activator, enhanced the transformation to CML-BC by mediating cell differentiation arrest. ASF1A expression was aberrantly increased in bone marrow samples from CML-BC patients compared with newly diagnosed CML-chronic phase (CP) patients. ASF1A inhibited cell differentiation and promoted CML development in vivo. Mechanistically, we identified ASF1A as a coactivator of the Notch transcriptional complex that induces H3K56ac modification in the promoter regions of Notch target genes, and subsequently enhanced RBPJ binding to these promoter regions, thereby enhancing Notch signaling activation to mediate differentiation arrest in CML cells. Thus, our work suggests that targeting ASF1A might represent a promising therapeutic approach and a biomarker to detect disease progression in CML patients.

Automated summary

ASF1A was found to be aberrantly expressed in CML-BC patients and enhanced the transformation to CML-BC by mediating cell differentiation arrest. This study also revealed that ASF1A functions as a coactivator of the Notch transcriptional complex, enhancing Notch signaling activation to mediate differentiation arrest in CML cells. These findings suggest that targeting ASF1A might represent a promising therapeutic approach and ASF1A could serve as a biomarker for disease progression in CML patients.