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Written by | Qi
Adaptive B cell responses rely on a diverse repertoire of mature B cells, and to ensure the production of sufficient quantity and quality of mature B cells, developing B cells undergo alternating cycles
of proliferation and differentiation.
This process requires specific integration of cytokine and antigen receptor signaling pathways to drive appropriate proliferation and establish developmental checkpoints after recombination to ensure the generation of functional, non-autoreactive B-cell receptors (BCRs).
。 These diverse and complex roles affect the B lymphatic transcription factors that shape B cell development, and they can modulate epigenetic and transcriptional landscapes by recruiting transcriptional cofactors, and co-repressors play a key role in this process by linking histone deacetylase to transcription factors, allowing them to drive gene suppression
.
However, the role of specific co-inhibitors in regulating development, as well as the mechanisms by which they isolate, proliferate, and differentiate, remain understood
.
The nuclear receptor co-inhibitors NCOR1 and NCOR2 interact with a variety of transcription factors, suggesting that NCOR1/2 may have a ubiquitous but stage-specific role
during development.
It should be noted that mutations and deletions of NCOR1/2 have been found in B-cell malignancies, suggesting that NCOR1/2 may play an important tumor suppressor role [1, 2], however, their role in malignant transformation remains unknown
.
Recently, Michael A.
Farrar's team from the University of Minnesota published an article in the journal Nature Immunology titled "Immunology.
" Nuclear corepressors NCOR1/NCOR2 regulate B cell development, maintain genomic integrity and prevent transformation of them A B-cell conditional knockout mouse model demonstrated how NCOR1/2 is involved in controlling various stages of B-cell development and their role in
B-cell acute lymphoblastic leukemia (B-ALL).
To understand the role of NCOR1 and NCOR2 during B-cell development, the authors generated B-cell conditionally knockout Ncor1 or Ncor2, Ncor1/2 double-knockout mice, and mice with single allele deficiency to assess gene dose relationships
。 The authors found no change in the number of pro-B and pro-B/pre-B progenitor B cells in NCOR1 KO, NCOR2 KO, NCOR1 het/NCOR2 KO, and NCOR1 KO/NCOR2 het mice, but NCOR1/2 DKO resulted in a significant reduction in these cells, and the number of immature B cells in NCOR1 KO/NCOR2 het mice was significantly reduced, while pre-B cells were unaffected
。 In addition, the authors also found that Ki67 expression decreased in DKO progenitor B cells, cell frequency with kappa light chains decreased, and lambda chain usage increased accordingly
.
These data suggest that NCOR has a pervasive and critical role
in the proliferation and differentiation stages of B cell development.
To assess transcriptional and epigenetic networks regulated by NCOR1/2, the authors found through scRNA-seq and scATAC-seq that NCOR1/2 DKO leads to pre-BCR signaling pathway defects and activation of the STAT5 and p53 pathways, as well as higher levels of Rag1/2 expression with increased
accessibility 。 To understand whether abnormal regulation of Rag1/2 expression leads to genomic instability, the authors performed genome-wide sequencing of genomic DNA extracted from WT and NCOR DKO B cells, which increased the number of structural variants in NCOR DKO B cells, while causing deletion of Ercc2 (one of the main members of the nucleotide excision repair system), and found its specific recombinant signal sequence in the deletion region.
Indicates a possible off-target effect of RAG
.
Thus, NCOR1/2 plays an important role in limiting Rag1/2 chromatin accessibility and gene expression, while dysregulation of Rag1/2 is associated with
increased structural variation that may be attributed to off-target effects of RAG.
Since NCOR1 mutations and deletions are common in human B-cell malignancies, the authors utilized Stat5b-CA × CD79a-Cre × a mouse model of Ncor1FL/+ leukemia (manifesting as a mixture of B-cell and non-B-cell leukemia).
to detect whether deletion of the Ncor1 allele promotes increased transformation and reduced
survival.
B-cell leukemia has variable CD19 expression and is CD93+, while non-B-cell leukemia is CD90.
2+, but predominantly CD3- and expresses variable amounts of B220
.
Most Stat5b-CA × Cd79a-Cre × Ncor1 FL/FL leukemia cells express increased IL-7R levels
compared to Stat5b-CA × Cd79a-Cre × Ncor1FL/+ leukemia cells or WT B cells.
These findings suggest that NCOR1 can prevent transformation because the loss of Ncor1 can initiate leukaemia transformation
in synergy with STAT5 activation.
Finally, the authors wondered if the above changes would also apply to humans
.
The authors found that 16 of the 28 human B-ALL samples with NCOR1 mutations had intrachromosomal structural variations, while 3 of the 7 NCOR2 mutant samples had intrachromosomal structural variations
.
They also found significantly elevated expression of FOXO1 and FOXO1 target genes (RAG1, RAG2, and IL7R) of NCOR1 or NCOR2-deficient B-ALL compared to B-ALL with WT NCOR1/2.
Since NCOR is recruited to inhibit target gene transcription, deletion or mutation of NCOR1 or NCOR2 in B-ALL may lead to increased
accessibility and susceptibility to RAG-mediated DNA damage.
In addition, they observed that patients with NCOR1 expression below median had worse
overall survival compared to patients with higher median expression.
Together, this work demonstrates how the nuclear co-inhibitor NCOR1/2 coordinates proper B cell differentiation and protects genome integrity
during B cell development.
Original link: https://doi.
org/10.
1038/s41590-022-01343-7
Platemaker: Eleven
References
1.
Mullighan, C.
G.
et al.
CREBBP mutations in relapsed acute lymphoblastic leukaemia.
Nature 471, 235–241 (2011).
2.
Reddy, A.
et al.
Genetic and functional drivers of diffuse large B cell lymphoma.
Cell 171, 481 (2017).
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