A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia

Eldeeb, Mohamed; Ouyang, Yong; Guzzi, Nicola; Ngoc, Phuong Cao Thi; Konturek-Ciesla, Anna; Kristiansen, Trine A.; Muthukumar, Sowndarya; Magee, Jeffrey A.; Bellodi, Cristian; Yuan, Joan; Bryder, David

doi:10.1016/j.celrep.2023.112099

Cited by 8 publications

(9 citation statements)

References 72 publications

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“…Nevertheless, since our data did detect the same top gene ontology terms as previous datasets from other tissues, they serve as confirmatory evidence in the context of B cell precursors. A recent LIN28B interactome study in hematopoietic progenitors expressing the oncogenic fusion protein MLL-ENL identified both Rps9 and Rpl23 transcripts as direct targets of LIN28B, offering further support to our findings in the hematopoietic system ( 39 ). Despite these limitations, our approach resulted in the identification of a relevant regulatory axis for early-life B lymphopoiesis.…”

Section: Discussionsupporting

confidence: 86%

“…LIN28B bound mRNA targets have been linked to both translational increase and decrease in a context dependent manner ( 22 – 24 , 27 , 31 , 39 ). In the case of ribosomal protein transcripts, enhanced protein translation was shown by SILAC (stable isotope labeling using amino acid in cell culture) metabolic labeling ( 22 ) as well as polysome profiling ( 31 ).…”

Section: Resultsmentioning

confidence: 99%

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Enhanced protein synthesis is a defining requirement for neonatal B cell development

et al. 2023

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The LIN28B RNA binding protein exhibits an ontogenically restricted expression pattern and is a key molecular regulator of fetal and neonatal B lymphopoiesis. It enhances the positive selection of CD5+ immature B cells early in life through amplifying the CD19/PI3K/c-MYC pathway and is sufficient to reinitiate self-reactive B-1a cell output when ectopically expressed in the adult. In this study, interactome analysis in primary B cell precursors showed direct binding by LIN28B to numerous ribosomal protein transcripts, consistent with a regulatory role in cellular protein synthesis. Induction of LIN28B expression in the adult setting is sufficient to promote enhanced protein synthesis during the small Pre-B and immature B cell stages, but not during the Pro-B cell stage. This stage dependent effect was dictated by IL-7 mediated signaling, which masked the impact of LIN28B through an overpowering stimulation on the c-MYC/protein synthesis axis in Pro-B cells. Importantly, elevated protein synthesis was a distinguishing feature between neonatal and adult B cell development that was critically supported by endogenous Lin28b expression early in life. Finally, we used a ribosomal hypomorphic mouse model to demonstrate that subdued protein synthesis is specifically detrimental for neonatal B lymphopoiesis and the output of B-1a cells, without affecting B cell development in the adult. Taken together, we identify elevated protein synthesis as a defining requirement for early-life B cell development that critically depends on Lin28b. Our findings offer new mechanistic insights into the layered formation of the complex adult B cell repertoire.

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Section: Discussionsupporting

confidence: 86%

Section: Resultsmentioning

confidence: 99%

Enhanced protein synthesis is a defining requirement for neonatal B cell development

et al. 2023

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“…Nevertheless, since our data did detect the same top gene ontology terms as previous datasets from other tissues, they serve as confirmatory evidence in the context of B cell precursors. A recent LIN28B interactome study in hematopoietic progenitors expressing the oncogenic fusion protein MLL-ENL identified both Rps9 and Rpl23 transcripts as direct targets of LIN28B, offering further support to our findings in the hematopoietic system (40). Despite these limitations, our approach resulted in the identification of a relevant regulatory axis for early-life B lymphopoiesis.…”

Section: Discussionsupporting

confidence: 86%

“…LIN28B bound mRNA targets have been linked to both translational increase and decrease in a context dependent manner (22, 24, 27, 31, 39, 40). In the case of ribosomal protein transcripts, enhanced protein translation was shown by SILAC (stable isotope labeling using amino acid in cell culture) metabolic labeling (22) as well as polysome profiling (31).…”

Section: Resultsmentioning

confidence: 99%

“…In particular, our findings implicate the ribosome as a potential target for LIN28B regulation in B cell progenitors. LIN28B enhances protein synthesis in the small Pre-B and Imm-B stages of B cell development LIN28B bound mRNA targets have been linked to both translational increase and decrease in a context dependent manner (22,24,27,31,39,40). In the case of ribosomal protein transcripts, enhanced protein translation was shown by SILAC (stable isotope labeling using amino acid in cell culture) metabolic labeling (22) as well as polysome profiling (31).…”

Section: The Lin28b Mrna Interactome In Primary B Cell Precursors Is ...mentioning

confidence: 99%

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Enhanced protein synthesis is a defining requirement for neonatal B cell development

Åkerstrand

Boldrin

Montano

et al. 2022

Preprint

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Protein synthesis is a stringently regulated process that fundamentally dictates capacity for cellular growth. Rapid fluctuations in cell size and proliferation characterize B cell development. However, little is known about how ribosomal control may impact this process. Here, we identify elevated protein synthesis as a defining feature of early-life B cell development and a determinant for the output of self-reactive CD5+ B-1 cells in mice. Interactome analyses in primary B cell precursors showed direct binding of the heterochronic RNA binding protein LIN28B to ribosomal protein transcripts, which correlated with their elevated protein expression in vivo. Genetic perturbations demonstrated that LIN28B is both necessary and sufficient to elevate protein synthesis during the small Pre-B and immature B cell stages. Interestingly, IL-7 signaling was the dominant driver of the c-MYC/ribosome axis in earlier stages and masked LIN28B induced protein synthesis in Pro-B cells. Finally, we demonstrated that subdued protein synthesis was detrimental for neonatal B cell development and the output of self-reactive B-1 cells, without affecting the adult. Thus, LIN28B elevates ribosomal capacity to shape the naive B cell repertoire in neonatal life.

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Post-transcriptional (re)programming of B lymphocyte development: From bench to bedside?

Welsh,

Muljo

2024

Advances in Immunology

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A fetal tumor suppressor axis abrogates MLL-fusion-driven acute myeloid leukemia

Cited by 8 publications

References 72 publications

Enhanced protein synthesis is a defining requirement for neonatal B cell development

Enhanced protein synthesis is a defining requirement for neonatal B cell development

Enhanced protein synthesis is a defining requirement for neonatal B cell development

Post-transcriptional (re)programming of B lymphocyte development: From bench to bedside?

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