Yin Ye

Acute monocytic leukemia (AML-M5) is a type of acute myeloid leukemia, characterized by a dominance of monocytes in the bone marrow and peripheral blood. AML-M5 exhibits a poor prognosis compared to other AML subtypes. Despite clinical recognition, current research on AML-M5 remains relatively limited, and its underlying pathogenic mechanisms are not yet fully understood. In this study, we uncover a distinct and heightened expression of CBX4, a core component of PRC1, in the peripheral blood of individuals diagnosed with AML-M5. By generating cbx4 overexpression transgenic and deleted mutant zebrafish lines, we observe elevated cbx4 expression in monocyte/macrophage, selectively modulating their production during zebrafish hematopoiesis. Notably, aging zebrafish with cbx4 overexpression exhibit a progression to AML-M5-like hematopoiesis. Further mechanistic analyses reveal that Cbx4 regulates the fate of monocyte/macrophage lineage by suppressing runx1 expression. This suppression is achieved through the recruitment of HDAC to the runx1 promoter via cbx4, resulting in the down-regulation of the H3K27 acetylation level of runx1. These findings offer novel insights, providing potential avenues for risk assessment and molecular diagnosis of AML-M5 leukemia. Moreover, CBX4 emerges as a promising target for the diagnosis and treatment of AML-M5 leukemia.

Acute promyelocytic leukemia (APL) is driven by the specific fusion gene PML-RARA produced by chromosomal translocation. Three classic isoforms, L, V, and S, are found in more than 95% of APL patients. However, atypical PML-RARA isoforms are usually associated with uncertain disease progression and treatment prognosis. Recently, we found a novel PML-RARA isoform (named PA) in a patient with atypical clinical characteristics of APL. In order to provide valuable insights for clinical treatment, we constructed the novel PML-RARA isoform zebrafish model for all-trans retinoic acid (ATRA) treatment experiments and comparison with classical isoforms. We found that the effect of PA PML-RARA on the expression of neutrophil-related genes was comparable with classical isoforms and ATRA treatment worked successfully in the zebrafish model. Sequence and structure analysis of the PA protein confirmed its similarity to classical isoforms and the fusion site of PA PML-RARA did not affect the ATRA binding site. As expected, the patient achieved complete remission within two months of treatment with ATRA in combination with arsenic trioxide (ATO) and had a favorable prognosis during the three-year follow-up. Our study highlights the accuracy and efficacy of the PML-RARA zebrafish model in combination with protein structure prediction in support of clinical treatment strategies.