FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome

Myelodysplastic syndromes (MDSs) are malignant hematopoietic stem and progenitor cell (HSPC) disorders that lead to ineffective blood production with poor outcomes. We previously showed that F-box only protein 11 (FBXO11) is downregulated in MDS, and here we report how this event contributes to disease progression. Integration of multiomics data revealed that the SCF-FBXO11 complex regulates spliceosome and ribosome components in a nucleophosmin 1 (NPM1)-centric network. FBXO11 facilitates the ubiquitylation of NPM1, whereby deletion of FBXO11 results in the reorganization of NPM1 and a de-repression of alternative splicing. Label-free total quantitative proteomics demonstrated that the FBXO11-NPM1 interactome was markedly downregulated in cells from patients with CD34+ MDS. In addition, we discovered that MYC was evicted from the FBXO11 promoter by TLR2 activation, revealing that it was a MYC target gene and explaining why FBXO11 expression was decreased in MDS. In MDS mouse models, genetic ablation of Fbxo11 exacerbated neutropenia concomitant with a profound decrease in NPM1 protein levels. Finally, we discovered rare mutations in FBXO11, which mapped to a previously unstudied functional intrinsically disordered region (IDR) in the N-terminus responsible for binding NPM1. These data support a model in which FBXO11 rewires RNA binding and ribosomal subnetworks through ubiquitylation of NPM1, ultimately restricting MDS progression.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2026-01-15
DOI
https://doi.org/10.1172/jci193636
Primary Topic
Acute Myeloid Leukemia Research
Type
article
Field-Weighted Citation Impact
0.00

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article

FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome

Michael Schieber, Guolian Kang, Anthony A. High, Shilpa Narina et al.
Journal of Clinical Investigation
Acute Myeloid Leukemia Research
article

FBXO11 suppression rewires an NPM1-centered interactome influencing the progression of myelodysplastic syndrome

Michael Schieber, Guolian Kang, Anthony A. High, Shilpa Narina, Jacob Steele, A Schild, Anitria Cotton, lance Palmer, Sarah Aminov, Vishwajeeth Pagala, Trent Hall, Madeline Niederkorn, John D. Crispino, Laura J. Janke, Erin McGovern, Cui Wu, Mitchell J. Weiss, Lavanya Bezavada, Aaron B. Taylor, Peng Xu, Amit Verma, Zuo-Fei Yuan, Raajit K. Rampal, Lahiri Konada, Peng Ji, Yingxue Fu, Sandeep Gurbuxani, Shondra M. Pruett-Miller, Jinbin Zhai
article en

Abstract

Myelodysplastic syndromes (MDSs) are malignant hematopoietic stem and progenitor cell (HSPC) disorders that lead to ineffective blood production with poor outcomes. We previously showed that F-box only protein 11 (FBXO11) is downregulated in MDS, and here we report how this event contributes to disease progression. Integration of multiomics data revealed that the SCF-FBXO11 complex regulates spliceosome and ribosome components in a nucleophosmin 1 (NPM1)-centric network. FBXO11 facilitates the ubiquitylation of NPM1, whereby deletion of FBXO11 results in the reorganization of NPM1 and a de-repression of alternative splicing. Label-free total quantitative proteomics demonstrated that the FBXO11-NPM1 interactome was markedly downregulated in cells from patients with CD34+ MDS. In addition, we discovered that MYC was evicted from the FBXO11 promoter by TLR2 activation, revealing that it was a MYC target gene and explaining why FBXO11 expression was decreased in MDS. In MDS mouse models, genetic ablation of Fbxo11 exacerbated neutropenia concomitant with a profound decrease in NPM1 protein levels. Finally, we discovered rare mutations in FBXO11, which mapped to a previously unstudied functional intrinsically disordered region (IDR) in the N-terminus responsible for binding NPM1. These data support a model in which FBXO11 rewires RNA binding and ribosomal subnetworks through ubiquitylation of NPM1, ultimately restricting MDS progression.

Journal of Clinical InvestigationVol. 136(2)
Northwestern University (US), Albert Einstein College of Medicine (US), St. Jude Children's Research Hospital (US), Memorial Sloan Kettering Cancer Center (US), Montefiore Medical Center (US), Northwestern Medicine Lake Forest Hospital (US), Soochow University (CN), University of Chicago (US), Proteogenomics Research Institute for Systems Medicine (US), International Society for Experimental Hematology (US), Center for Genomic Science (IT), Montefiore Einstein Comprehensive Cancer Center
Memorial Sloan-Kettering Cancer Center, University of Washington, Edward P. Evans Foundation, American Lebanese Syrian Associated Charities, National Institutes of Health, University of California, San Diego
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