Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
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Curated by eLife
Evaluation Summary:
This is an outstanding manuscript evaluating a mutation commonly seen in AML and MDS in a spliceosome protein called SF3B1. The authors link this spliceosome mutation to altered transcripts and ultimately to cell cycle proteins and differentiation. This paper will be of high interest for oncologists in that it demonstrates that AML and MDS cells with this mutation can be targeted in a precision medicine approach.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
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.
Funding:
This work was supported by Cincinnati Children’s Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle’s Angel Foundation for Cancer Research, and Edward P. Evans Foundation grants to DTS. AV is supported by Edward P. Evans Foundation, National Institute of Health (R01HL150832, R01HL139487, R01CA275007), Leukemia and Lymphoma Society, Curis and a gift from the Jane and Myles P. Dempsey family. AP and JB are supported by Blood Cancer UK (grants 13042 and 19004). GC is supported by a training grant from NYSTEM. We acknowledge support of this research from The Einstein Training Program in Stem Cell Research from the Empire State Stem Cell Fund through New York State Department of Health Contract C34874GG. MS is supported by a National Institute of Health Research Training and Career Development Grant (F31HL132420).
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Evaluation Summary:
This is an outstanding manuscript evaluating a mutation commonly seen in AML and MDS in a spliceosome protein called SF3B1. The authors link this spliceosome mutation to altered transcripts and ultimately to cell cycle proteins and differentiation. This paper will be of high interest for oncologists in that it demonstrates that AML and MDS cells with this mutation can be targeted in a precision medicine approach.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This is an outstanding manuscript evaluating a mutation commonly seen in AML and MDS in the splicesome SF3B1. The authors demonstrate that this mutation leads to a shift in the production of a long-form of IRAK4 (called IRAK4-L), which is part of inflammatory signaling in immune cells. They demonstrate that IRAK4-L stabilizes the cell cycle protein CDK2, and targeting IRAK4-L with an inhibitor can induce differentiation and slow clonal uptake in murine transplantation models. The text is easy to read, there are ample supplemental figures to help explain complicated experiments. Overall this manuscript is likely to be of high interest for oncologists in that it demonstrates that AML and MDS cells with an SF3B1 mutation can be targeted in a precision medicine approach via inhibition of IRAK4. There are no …
Reviewer #1 (Public Review):
This is an outstanding manuscript evaluating a mutation commonly seen in AML and MDS in the splicesome SF3B1. The authors demonstrate that this mutation leads to a shift in the production of a long-form of IRAK4 (called IRAK4-L), which is part of inflammatory signaling in immune cells. They demonstrate that IRAK4-L stabilizes the cell cycle protein CDK2, and targeting IRAK4-L with an inhibitor can induce differentiation and slow clonal uptake in murine transplantation models. The text is easy to read, there are ample supplemental figures to help explain complicated experiments. Overall this manuscript is likely to be of high interest for oncologists in that it demonstrates that AML and MDS cells with an SF3B1 mutation can be targeted in a precision medicine approach via inhibition of IRAK4. There are no major weaknesses in the manuscript.
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Reviewer #2 (Public Review):
Choudhary et al describe a novel downstream impact of SF3B1 splicing mutations in MDS. Their findings support exon 6 retention in IRAK4, leading to TRAF6 mediated CDK2 ubiquitination. Next, their results demonstrate that IRAK4 inhibitors can reverse these effects to therapeutic benefit in vitro and in-vivo in SF3B1 mutant MDS models, including primary cells. Overall, the manuscript is beautifully written and their conclusions will be of broad interest to hematologists, immunologists and the scientific community at large.
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