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Activation of targetable inflammatory immune signaling is seen in Myelodysplastic Syndromes with SF3B1 mutations [article]

Gaurav S Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Leya Schwartz, Violetta Steeples, Robert N Booher (+16 others)
2022 bioRxiv   pre-print

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https://web.archive.org/web/20220318213314/https://www.biorxiv.org/content/biorxiv/early/2022/03/09/2022.03.09.483595.full.pdf

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AbstractBackgroundMutations in the SF3B1 splicing factor are commonly seen in Myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML), yet the specific oncogenic pathways activated by missplicing have not been fully elucidated. Inflammatory immune pathways have been shown to play roles in pathogenesis of MDS, though the exact mechanisms of their activation in splicing mutant cases are not well understood.MethodsRNA-seq data from SF3B1 mutant samples was analyzed and functional roles of
more » ... IRAK4 isoforms were determined. Efficacy of IRAK4 inhibition was evaluated in pre-clinical models of MDS/AMLResultsRNA-seq splicing analysis of innate immune mediators in SF3B1 mutant MDS samples revealed retention of full-length exon 6 of interleukin-1 receptor-associated kinase 4 (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 proteosomal 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.ConclusionsSF3B1 mutation leads to expression of a therapeutically targetable, longer, oncogenic IRAK4 isoform in AML/MDS models.
doi:10.1101/2022.03.09.483595 fatcat:dasqw2bhozdtdpuqowqrd5yr4a
Citation

Gaurav S Choudhary, Andrea Pellagatti, Bogos Agianian, Molly A Smith, Tushar D Bhagat, Shanisha Gordon-Mitchell, Sanjay Pandey, Nishi Shah, Srinivas Aluri, Leya Schwartz, Violetta Steeples, Robert N Booher, Murali Ramachandra, Maria Elena Samson, Milagros Carbajal, Kith Pradhan, Teresa V. Bowman, Manoj M Pillai, Britta Will, Amittha Wickrema, Aditi Shastri, Robert Bradley, Robert Martell, Ulrich G. Steidl, Evripidis Gavathiotis, Jacqueline Boultwood, Daniel T. Starczynowski, Amit Verma. "Activation of targetable inflammatory immune signaling is seen in Myelodysplastic Syndromes with SF3B1 mutations." bioRxiv (2022)