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

• Published in: Cell death & disease Vol. 13; no. 10; pp. 842 - 9
• Main Authors: Yin, Xiaolin, Zhou, Minran, Zhang, Lu, Fu, Yue, Xu, Man, Wang, Xiaoming, Cui, Zelong, Gao, Zhenxing, Li, Miao, Dong, Yuting, Feng, Huimin, Ma, Sai, Chen, Chunyan
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.10.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/109; 13/31; 13/51; 13/89; 38/77; 38/91; 631/67/1990/283/1896; 631/80/86; 64/60; 82/80; Antibodies; Antigens; Biochemistry; Biomarkers; Biomedical and Life Sciences; Blast crisis; Blast Crisis - genetics; Bone marrow; Cell Biology; Cell Culture; Cell Cycle Proteins - genetics; Cell differentiation; Cell Differentiation - genetics; Chromosomes; Chronic myeloid leukemia; Fluorides; Gene expression; Genetic transformation; Hematology; Histone Chaperones; Histones; Hospitals; Humans; Immunology; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Life Sciences; Molecular Chaperones - genetics; Myeloid leukemia; Patients; Proteins
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-022-05234-5

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.