Induced lineage promiscuity undermines the efficiency of all-trans-retinoid-acid-induced differentiation of acute myeloid leukemia

Yijia Tang,Xin Tian,Zihan Xu,Junke Cai,Han Liu,Nan Liu,Zhu Chen,Saijuan Chen,Feng Liu

doi:10.1016/j.isci.2021.102410

Abstract

SummaryAll-trans retinoid acid (ATRA) can induce terminal differentiation of acute promyelocytic leukemia (APL), also known as the M3 subtype of acute myeloid leukemia (AML). However, non-APL types of AML respond poorly to ATRA-induced differentiation, and the mechanism underlying cell-type-specific resistance against ATRA remains unclear. Here, we use single-cell transcriptome analysis to compare the differentiation trajectories of two AML cell types during ATRA treatment. We show that in NB4 (APL/AML-M3) cells, ATRA activates canonical myeloid lineage factors—including SPI1, CEBPE, and STAT1—to direct near-normal differentiation toward mature granulocytes. By contrast, in HL60 (AML-M2) cells, ATRA-induced differentiation is incomplete and promiscuous, which is characterized by coinduction of both myelopoiesis and lymphopoiesis gene expression programs, as well as transient activation of cis-regulatory elements associated with myeloid differentiation. Our study suggests that the differentiation inducing capacity of ATRA in certain subtypes of AML may be compromised by therapy-induced lineage promiscuity.

Highlights

The hematopoietic system is generated by a hierarchy of stem/progenitor cells in the bone marrow, which proliferate and differentiate along distinct cell lineages, leading to terminal differentiation of a multitude of specialized cell types of the myeloid compartment and the lymphoid compartment (e.g. B cells, T cells, and natural killer cells) (Laurenti and Gottgens, 2018)
In non-acute promyelocytic leukemia (APL) types of acute myeloid leukemia (AML), a lack of therapeutic effect of all-trans retinoid acid (ATRA) is generally thought to be the lack of promyelocytic leukemia (PML)-RARA mutation, in principle, terminal differentiation programs may still be activated by ATRA via the intrinsic retinoid signaling pathway
Overview of ATRA-regulated gene expression programs in NB4 and HL60 leukemia cell lines To systematically compare ATRA-regulated gene expression programs between HL60 and NB4 cells, we first performed a side-by-side mRNA-seq experiment using each cell line cultured with 1 mM of ATRA for 1/3/ 6 days (Figure 1A)

Summary

Introduction

The hematopoietic system is generated by a hierarchy of stem/progenitor cells in the bone marrow, which proliferate and differentiate along distinct cell lineages, leading to terminal differentiation of a multitude of specialized cell types of the myeloid compartment (e.g. granulocytes, monocytes, macrophages, erythrocytes, mast cells, and dendritic cells) and the lymphoid compartment (e.g. B cells, T cells, and natural killer cells) (Laurenti and Gottgens, 2018). It has been suggested that leukemia often originates from aberrant differentiation blockage of hematopoietic progenitor cells, and unblocking such blockage may provide an efficient means of cure (Tenen, 2003) This strategy, known as differentiation therapy, has been successfully applied in the treatment of acute promyelocytic leukemia (APL), known as acute myeloid leukemia (AML)-M3 subtype, using all-trans retinoid acid (ATRA) in combination with arsenic compounds (Chen and Chen, 2017; Huang et al, 1988; Petrie et al, 2009; Wang and Chen, 2008). In non-APL types of AML, a lack of therapeutic effect of ATRA is generally thought to be the lack of PML-RARA mutation, in principle, terminal differentiation programs may still be activated by ATRA via the intrinsic retinoid signaling pathway.

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Discussion

Conclusion