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  1. 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.)

  2. 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.

  3. 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.