TY - JOUR
T1 - Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
AU - Choudhary, Gaurav S.
AU - Pellagatti, Andrea
AU - Agianian, Bogos
AU - Smith, Molly A.
AU - Bhagat, Tushar D.
AU - Gordon-Mitchell, Shanisha
AU - Sahu, Srabani
AU - Pandey, Sanjay
AU - Shah, Nishi
AU - Aluri, Srinivas
AU - Aggarwal, Ritesh
AU - Aminov, Sarah
AU - Schwartz, Leya
AU - Steeples, Violetta
AU - Booher, Robert N.
AU - Ramachandra, Murali
AU - Samson, Maria
AU - Carbajal, Milagros
AU - Pradhan, Kith
AU - Bowman, Teresa V.
AU - Pillai, Manoj M.
AU - Will, Britta
AU - Wickrema, Amittha
AU - Shastri, Aditi
AU - Bradley, Robert K.
AU - Martell, Robert E.
AU - Steidl, Ulrich G.
AU - Gavathiotis, Evripidis
AU - Boultwood, Jacqueline
AU - Starczynowski, Daniel T.
AU - Verma, Amit
N1 - Publisher Copyright:
© Choudhary, Pellagatti et al.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
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U2 - 10.7554/eLife.78136
DO - 10.7554/eLife.78136
M3 - Article
C2 - 36040792
AN - SCOPUS:85137126309
SN - 2050-084X
VL - 11
JO - eLife
JF - eLife
M1 - e78136
ER -