Biological Sciences Division
Published August 30, 2022 | Version v1
Journal article Open

Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations

Creators

  • 1. Albert Einstein College of Medicine
  • 2. University of Oxford
  • 3. Cincinnati Children's Hospital Medical Center
  • 4. Curis Inc.
  • 5. Aurigene Inc.
  • 6. Yale University
  • 7. University of Chicago

Description

Background: Mutations in the SF3B1 splicing factor are commonly seen in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), yet the specific oncogenic pathways activated by mis-splicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in the pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.

Methods: RNA-seq data from SF3B1 mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (IRAK4) isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in preclinical models of MDS/AML.

Results: RNA-seq splicing analysis of SF3B1 mutant MDS samples revealed retention of full-length exon 6 of IRAK4, a critical downstream mediator that links the Myddosome to inflammatory NF-kB activation. Exon 6 retention leads to a longer isoform, encoding a protein (IRAK4-long) that contains the entire death domain and kinase domain, leading to maximal activation of NF-kB. Cells with wild-type SF3B1 contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in SF3B1 mutant cells induces TRAF6 activation leading to K63-linked ubiquitination of CDK2, associated with a block in hematopoietic differentiation. Inhibition of IRAK4 with CA-4948, leads to reduction in NF-kB activation, inflammatory cytokine production, enhanced myeloid differentiation in vitro and reduced leukemic growth in xenograft models.

Conclusions: SF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.

Notes

Due to the large number of authors, only the first 20 and the University of Chicago authors are included on the above author list. Please download the article for the complete list of authors.

Data availability

Publicly available dataset was used (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114922).

The following previously published data sets were used:

Pellagatti A Armstrong RN Steeples V Sharma E Repapi E Singh S Sanchi A Radujkovic A Horn P Dolatshad H Roy S Broxholme J Lockstone H Taylor S Giagounidis A Vyas P Schuh A Hamblin A Papaemmanuil E Killick S Malcovati L Hennrich ML Gavin AC Luft T Hellström-Lindberg E Cazzola M Smith CWJ Smith S Boultwood J Ad HO (2018) NCBI Gene Expression Omnibus ID GSE114922. Impact of spliceosome mutations on RNA splicing in myelodysplasia: dysregulated genes/pathways and clinical associations. https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114922

Files

elife-78136-v1.pdf

Files (6.6 MB)

Name Size Download all
Article
md5:7295b87bfe4a1718f810a14573777cf9
6.4 MB Preview Download
md5:0b09ac431caee8f18b8f6cd3d48c4017
215.7 kB Preview Download

Additional details

Identifiers

DOI
10.7554/eLife.78136
Other
oai:uchicago.tind.io:10692

Related works

Cites
https://doi.org/10.1101/2022.03.09.483595 (URL)

Funding

National Cancer Institute
R01CA275007
Edward P. Evans Foundation
Leukemia and Lymphoma Society
TRP
National Heart, Lung, and Blood Institute
R01HL150832
National Heart, Lung, and Blood Institute
R01HL139487
National Heart, Lung, and Blood Institute
RO1HL111103
National Heart, Lung, and Blood Institute
R35HL135787
National Institute of Diabetes and Digestive and Kidney Diseases
RO1DK102759
Blood Cancer UK
13042
Blood Cancer UK
19004

UChicago Information

Division(s)
Biological Sciences Division
Department(s)
Cancer Biology, Medicine