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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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs2\">\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      RNA-seq data from\n                      <jats:italic>SF3B1<\/jats:italic>\n                      mutant samples was analyzed and functional roles of interleukin-1 receptor-associated kinase 4 (\n                      <jats:italic>IRAK4)<\/jats:italic>\n                      isoforms were determined. Efficacy of\n                      <jats:italic>IRAK4<\/jats:italic>\n                      inhibition was evaluated in preclinical models of MDS\/AML.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs3\">\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      RNA-seq splicing analysis of\n                      <jats:italic>SF3B1<\/jats:italic>\n                      mutant MDS samples revealed retention of full-length exon 6 of\n                      <jats:italic>IRAK4<\/jats:italic>\n                      , 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\n                      <jats:italic>SF3B1<\/jats:italic>\n                      contain smaller IRAK4 isoforms that are targeted for proteasomal degradation. Expression of IRAK4-long in\n                      <jats:italic>SF3B1<\/jats:italic>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs4\">\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      <jats:italic>SF3B1<\/jats:italic>\n                      mutation leads to expression of a therapeutically targetable, longer, oncogenic\n                      <jats:italic>IRAK4<\/jats:italic>\n                      isoform in AML\/MDS models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"abs5\">\n                    <jats:title>Funding:<\/jats:title>\n                    <jats:p>This work was supported by Cincinnati Children\u2019s Hospital Research Foundation, Leukemia Lymphoma Society, and National Institute of Health (R35HL135787, RO1HL111103, RO1DK102759, RO1HL114582), Gabrielle\u2019s 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).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.7554\/elife.78136","type":"journal-article","created":{"date-parts":[[2022,7,13]],"date-time":"2022-07-13T06:15:56Z","timestamp":1657692956000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.78136","source":"Crossref","is-referenced-by-count":75,"title":["Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5365-6706","authenticated-orcid":true,"given":"Gaurav S","family":"Choudhary","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044ntvm43","id-type":"ROR","asserted-by":"publisher"}],"name":"Blood Cancer Institute, Albert Einstein College of Medicine, Montefiore Medical Center","place":["The Bronx, United 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