SETBP1 overexpression acts in the place of class-defining mutations to drive FLT3-ITD–mutant AML

Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (...

Full description

Saved in:
Bibliographic Details
Published in:Blood advances 2021-05, Vol.5 (9), p.2412-2425
Main Authors: Pacharne, Suruchi, Dovey, Oliver M., Cooper, Jonathan L., Gu, Muxin, Friedrich, Mathias J., Rajan, Sandeep S., Barenboim, Maxim, Collord, Grace, Vijayabaskar, M.S., Ponstingl, Hannes, De Braekeleer, Etienne, Bautista, Ruben, Mazan, Milena, Rad, Roland, Tzelepis, Konstantinos, Wright, Penny, Gozdecka, Malgorzata, Vassiliou, George S.
Format: Article
Language:English
Subjects:
Acute Disease
Animals
DNA-Binding Proteins
Histone-Lysine N-Methyltransferase
Leukemia, Myeloid, Acute - genetics
Mice
Mutation
Myeloid Neoplasia
Nuclear Proteins - genetics
Nucleophosmin
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Advances in cancer genomics have revealed genomic classes of acute myeloid leukemia (AML) characterized by class-defining mutations, such as chimeric fusion genes or in genes such as NPM1, MLL, and CEBPA. These class-defining mutations frequently synergize with internal tandem duplications in FLT3 (FLT3-ITDs) to drive leukemogenesis. However, ∼20% of FLT3-ITD–positive AMLs bare no class-defining mutations, and mechanisms of leukemic transformation in these cases are unknown. To identify pathways that drive FLT3-ITD mutant AML in the absence of class-defining mutations, we performed an insertional mutagenesis (IM) screening in Flt3-ITD mice, using Sleeping Beauty transposons. All mice developed acute leukemia (predominantly AML) after a median of 73 days. Analysis of transposon insertions in 38 samples from Flt3-ITD/IM leukemic mice identified recurrent integrations at 22 loci, including Setbp1 (20/38), Ets1 (11/38), Ash1l (8/38), Notch1 (8/38), Erg (7/38), and Runx1 (5/38). Insertions at Setbp1 led exclusively to AML and activated a transcriptional program similar, but not identical, to those of NPM1-mutant and MLL-rearranged AMLs. Guide RNA targeting of Setbp1 was highly detrimental to Flt3ITD/+/Setbp1IM+, but not to Flt3ITD/+/Npm1cA/+, AMLs. Also, analysis of RNA-sequencing data from hundreds of human AMLs revealed that SETBP1 expression is significantly higher in FLT3-ITD AMLs lacking class-defining mutations. These findings propose that SETBP1 overexpression collaborates with FLT3-ITD to drive a subtype of human AML. To identify genetic vulnerabilities of these AMLs, we performed genome-wide CRISPR-Cas9 screening in Flt3ITD/+/Setbp1IM+ AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, and Hmgcr. Our study gives new insights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases. •SETBP1 overexpression activates a HOXA signature and collaborates with FLT3-ITD to drive AML in the absence of class-defining mutations.•AMLs driven by Setbp1 overexpression and Flt3-ITD have several specific genetic vulnerabilities, including Kdm1a and other druggable genes. [Display omitted]
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2020003443