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

Suruchi Pacharne, Oliver M. Dovey, Jonathan L. Cooper, Muxin Gu, Mathias J. Friedrich, Sandeep S. Rajan, Maxim Barenboim, Grace Collord, M. S. Vijayabaskar, Hannes Ponstingl, Etienne De Braekeleer, Ruben Bautista, Milena Mazan, Roland Rad, Konstantinos Tzelepis, Penny Wright, Malgorzata Gozdecka, George S. Vassiliou

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

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 fromFlt3-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/1/Setbp1IM1, but not to Flt3ITD/1/Npm1cA/1, AMLs. Also, analysis of RNAsequencing 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/1/Setbp1IM1 AMLs and identified potential therapeutic targets, including Kdm1a, Brd3, Ezh2, andHmgcr. Our study gives newinsights into epigenetic pathways that can drive AMLs lacking class-defining mutations and proposes therapeutic approaches against such cases.

Original languageEnglish
Pages (from-to)2412-2425
Number of pages14
JournalBlood Advances
Volume5
Issue number9
DOIs
StatePublished - 11 May 2021
Externally publishedYes

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