The Histone Deacetylase Inhibitor I13 Induces Differentiation of M2, M3 and M5 Subtypes of Acute Myeloid Leukemia Cells and Leukemic Stem-Like Cells

Abstract

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by reduced differentiation of myeloid cells and uncontrolled cell proliferation. AML is prone to drug resistance and has a high recurrence rate during treatment with cytarabine-based chemotherapy. Our study aims to explore the cell differentiation effect of a potent histone deacetylase inhibitor (HDACi), I13, and its possible mechanism on AML cell lines (Kasumi-1, KG-1, MOLM-13 and NB4). It has been shown that I13 can significantly inhibit proliferation and colony formation of these AML cells by inducing cell differentiation coupled with cell-cycle exit at G0/G1. Mechanically, I13 presented the property of HDAC inhibition, as assessed by the acetylation of histone H3, which led to the differentiation of Kasumi-1 cells. In addition, the HDAC inhibition of I13 likely dictated the activation of the antigen processing and presentation pathway, which maybe has the potential to promote immune cells to recognize leukemic cells and respond directly against leukemic cells. These results indicated that I13 could induce differentiation of M3 and M5 subtypes of AML cells, M2 subtype AML cells with t(8;21) translocation and leukemic stem-like cells. Therefore, I13 could be an alternative compound which is able to overcome differentiation blocks in AML.

I13 overrides resistance mediated by the T315I mutation in chronic myeloid leukemia by direct BCR-ABL inhibition

“…Though asciminib is a potent, orally bioavailable drug, it is inevitable that it will bring adverse reactions. In our previous study ( Ma et al, 2022 ), it was found that I13, a HDAC inhibitor, induced the differentiation of acute myeloid leukemia cells and inhibited cell proliferation. Herein, we present that I13 could overcome the differentiation block in CML cells harboring T315I-mutated BCR-ABL and wild-type BCR-ABL, characterized by the changed morphology and increased expression of CD11b, CD13, CD14, or CD15.…”

“…To quantify the genome-wide distribution of BaF3-T315I cells incubated with the indicated I13, mRNA sequencing was performed. As described previously, Ma et al, 2022 the cells were collected, and RNA was isolated from the cells. The Illumina genome analyzer was used to sequence the library of cDNA, and the expression levels of individual genes were normalized to the fragments per kilobase of transcript per million of the mapped data.…”

“…To quantify the genome-wide distribution of BaF3-T315I cells incubated with the indicated I13, mRNA sequencing was performed. As described previously, Ma et al, 2022 the cells were collected, and KEGG enrichment analysis of these DEGs was carried out using the R language clusterProfiler package, and an adjusted p-value of less that 0.05 was used as the cut-off criteria.…”

“…I13, an indole-3-butyric acid derivative and a potent HDACi ( Chen et al, 2021 ), was found to reduce the proliferation of acute myeloid leukemic cells by inducing cell differentiation in our previous study ( Ma et al, 2022 ). This current study investigated the inhibitory activity of I13 against CML cells with T315I-mutated and wild-type BCR-ABL and sought to understand the underlying mechanism of I13 action.…”

Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies

“…Similar effects in AML cell lines were also seen for the HDAC inhibitor I3 in AML cells with t(8; 21) translocation and MLL rearranged cell lines [ 179 ]; this study also described activation of the VEGF/MAPK (mitogen-activated protein kinase) signaling pathway. Finally, I13 seemed to modulate the antigen processing and presentation pathway [ 180 ].…”