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Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations

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 pa...

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Autores principales: Choudhary, Gaurav S, Pellagatti, Andrea, Agianian, Bogos, Smith, Molly A, Bhagat, Tushar D, Gordon-Mitchell, Shanisha, Sahu, Srabani, Pandey, Sanjay, Shah, Nishi, Aluri, Srinivas, Aggarwal, Ritesh, Aminov, Sarah, Schwartz, Leya, Steeples, Violetta, Booher, Robert N, Ramachandra, Murali, Samson, Maria, Carbajal, Milagros, Pradhan, Kith, Bowman, Teresa V, Pillai, Manoj M, Will, Britta, Wickrema, Amittha, Shastri, Aditi, Bradley, Robert K, Martell, Robert E, Steidl, Ulrich G, Gavathiotis, Evripidis, Boultwood, Jacqueline, Starczynowski, Daniel T, Verma, Amit
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427103/
https://www.ncbi.nlm.nih.gov/pubmed/36040792
http://dx.doi.org/10.7554/eLife.78136
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author Choudhary, Gaurav S
Pellagatti, Andrea
Agianian, Bogos
Smith, Molly A
Bhagat, Tushar D
Gordon-Mitchell, Shanisha
Sahu, Srabani
Pandey, Sanjay
Shah, Nishi
Aluri, Srinivas
Aggarwal, Ritesh
Aminov, Sarah
Schwartz, Leya
Steeples, Violetta
Booher, Robert N
Ramachandra, Murali
Samson, Maria
Carbajal, Milagros
Pradhan, Kith
Bowman, Teresa V
Pillai, Manoj M
Will, Britta
Wickrema, Amittha
Shastri, Aditi
Bradley, Robert K
Martell, Robert E
Steidl, Ulrich G
Gavathiotis, Evripidis
Boultwood, Jacqueline
Starczynowski, Daniel T
Verma, Amit
author_facet Choudhary, Gaurav S
Pellagatti, Andrea
Agianian, Bogos
Smith, Molly A
Bhagat, Tushar D
Gordon-Mitchell, Shanisha
Sahu, Srabani
Pandey, Sanjay
Shah, Nishi
Aluri, Srinivas
Aggarwal, Ritesh
Aminov, Sarah
Schwartz, Leya
Steeples, Violetta
Booher, Robert N
Ramachandra, Murali
Samson, Maria
Carbajal, Milagros
Pradhan, Kith
Bowman, Teresa V
Pillai, Manoj M
Will, Britta
Wickrema, Amittha
Shastri, Aditi
Bradley, Robert K
Martell, Robert E
Steidl, Ulrich G
Gavathiotis, Evripidis
Boultwood, Jacqueline
Starczynowski, Daniel T
Verma, Amit
author_sort Choudhary, Gaurav S
collection PubMed
description 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. 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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spelling pubmed-94271032022-08-31 Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations Choudhary, Gaurav S Pellagatti, Andrea Agianian, Bogos Smith, Molly A Bhagat, Tushar D Gordon-Mitchell, Shanisha Sahu, Srabani Pandey, Sanjay Shah, Nishi Aluri, Srinivas Aggarwal, Ritesh Aminov, Sarah Schwartz, Leya Steeples, Violetta Booher, Robert N Ramachandra, Murali Samson, Maria Carbajal, Milagros Pradhan, Kith Bowman, Teresa V Pillai, Manoj M Will, Britta Wickrema, Amittha Shastri, Aditi Bradley, Robert K Martell, Robert E Steidl, Ulrich G Gavathiotis, Evripidis Boultwood, Jacqueline Starczynowski, Daniel T Verma, Amit eLife Medicine 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. 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). eLife Sciences Publications, Ltd 2022-08-30 /pmc/articles/PMC9427103/ /pubmed/36040792 http://dx.doi.org/10.7554/eLife.78136 Text en © 2022, Choudhary, Pellagatti et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Medicine
Choudhary, Gaurav S
Pellagatti, Andrea
Agianian, Bogos
Smith, Molly A
Bhagat, Tushar D
Gordon-Mitchell, Shanisha
Sahu, Srabani
Pandey, Sanjay
Shah, Nishi
Aluri, Srinivas
Aggarwal, Ritesh
Aminov, Sarah
Schwartz, Leya
Steeples, Violetta
Booher, Robert N
Ramachandra, Murali
Samson, Maria
Carbajal, Milagros
Pradhan, Kith
Bowman, Teresa V
Pillai, Manoj M
Will, Britta
Wickrema, Amittha
Shastri, Aditi
Bradley, Robert K
Martell, Robert E
Steidl, Ulrich G
Gavathiotis, Evripidis
Boultwood, Jacqueline
Starczynowski, Daniel T
Verma, Amit
Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title_full Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title_fullStr Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title_full_unstemmed Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title_short Activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with SF3B1 mutations
title_sort activation of targetable inflammatory immune signaling is seen in myelodysplastic syndromes with sf3b1 mutations
topic Medicine
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9427103/
https://www.ncbi.nlm.nih.gov/pubmed/36040792
http://dx.doi.org/10.7554/eLife.78136
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