KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Abstract

Epigenetic abnormalities are frequently involved in the initiation and progression of cancers, including acute myeloid leukemia (AML). A subtype of AML, acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of promyelocytic leukemia–RA receptor fusion oncoprotein (PML-RARα). PML-RARα was reported as a transcription repressor through the interaction with nuclear receptor corepressor and histone deacetylase complexes leading to the mis-suppression of its target genes and differentiation blockage. Although previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri-methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, KDM5A binding was detected in 1889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes, primarily by controlling the H3K4me2 in the promoters and 5′ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455, on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to all-trans retinoic acid–induced differentiation. Our findings indicate that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.

JMJD family proteins in cancer and inflammation

“… 429 Likewise in leukemia, CPI-455 treatment sensitized acute promyelocytic leukemia (APL) cells to all-trans retinoic acid-induced differentiation. 430 Importantly, CPI-455 may also be applied in the context of inflammatory diseases. Dexmedetomidine (DEX) is frequently used to prevent excessive inflammatory response in sepsis-induced organ failure.…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…Chandra et al showed that NUP98 fusion proteins, including NUP98-KDM5A, form leukemia-related nuclear condensates, thus leading to leukemogenesis [85]. In addition to NUP98-KDM5A fusion, KDM5A has been shown to be involved in the progression of acute promyelocytic leukemia (APL) [86]. KDM5A contributes to the inhibition of differentiation in APL cells by repressing PML-RARα target genes via demethylating H3K4me2 [86].…”

“…In addition to NUP98-KDM5A fusion, KDM5A has been shown to be involved in the progression of acute promyelocytic leukemia (APL) [86]. KDM5A contributes to the inhibition of differentiation in APL cells by repressing PML-RARα target genes via demethylating H3K4me2 [86].…”

“…Conversely, KDM5 inhibitor CPI-455 or the knockout of KDM5A sensitizes APL cells to all-trans retinoic acid-induced differentiation [86].…”

Molecular and epigenetic alterations in normal and malignant myelopoiesis in human leukemia 60 (HL60) promyelocytic cell line model

“…Some of these leukemic cell lines hold the capacity to potentially differentiate into different hematopoietic lineages upon treatment with inducers. For example, the THP1 and U937 cell lines can be efficiently differentiated into macrophages using phorbol 12-myristate 13-acetate (PMA), and NB4 cells can be differentiated into granulocytes using all-trans retinoic acid (ATRA) or dimethyl sulfoxide (DMSO) ( Mendoza-Coronel and Castanon-Arreola, 2016 ; Xu et al, 2021 ). However, factors such as the culture media formulations, cell density, serum, and lack of homogeneous protocols affect the gene expression profile of cell lines.…”