RNA sequencing of AML cells treated with milademetan, selinexor and the combination of milademetan and selinexor

The tumor suppressor TP53 is frequently inactivated in cancers in a mutation-independent manner and is reactivated by inhibiting its negative regulators. We here co-target MDM2 with the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in synergistic induction of apoptosis in acute myeloid leukemia (AML). Surprisingly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, hig..., AML cell lines OCI-AML3, MOLM-13 TP53 wild-type and MOLM-13 TP53 p.R248Q cells were treated with milademetan, selinexor, and the combination of milademetan and selinexor for 12 hours. RNA samples were collected from those cells and subjected to RNA sequencing.
RNA sequencing
OCI-AML3, MOLM-13 TP53 wild-type, and R248Q mutant cells were treated with DMSO, milademetan, selinexor, or the combination of Mil + Sel for 12 hours. Cells were harvested and total RNA was extracted using QIAGEN RNeasy extraction kit from each sample (N = 3 for each treatment, N = 12 in total) according to the manufacturer’s protocol.
Barcoded, Illumina-compatible, strand-specific total RNA libraries were prepared using the TruSeq Stranded Total RNA Sample Preparation Kit (Illumina, San Diego, CA). Briefly, 1mg of DNase I treated total RNA was depleted of cytoplasmic and mitochondrial ribosomal RNA (rRNA) using Ribo-Zero Gold (Illumina). After purification, the RNA was fragmented using divalent cations and double-s..., , # RNA sequencing of AML cells treated with milademetan, selinexor and the combination of milademetan and selinexor

## Description of the data and file structure

There are 144 zipped fastq files (gz) and one metadata file. Please refer to the metadata file to annotate the data of interest. Please read the methods in the description of the datasets to understand and reproduce the data in the manuscript.

## Code/Software used in the study

Software packages to analyze our datasets are described in the method section.