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CBF-β is shown to regulate the ability of HIV-1 to evade host restriction mediated by the deaminase APOBEC3. Vif–CBF-β interaction an anti-HIV-1 target The transcription cofactor CBF-β (core binding factor β) regulates the DNA binding activity of RUNX family proteins. Two independent studies now show that CBF-β also regulates the ability of HIV-1 to evade host restriction mediated by the cDNA deaminase APOBEC3G, a host factor that blocks viral replication. They show that it associates with the HIV protein Vif, and is essential for the assembly of the Vif-Cul5 E3 ubiquitin ligase complex, which mediates the ubiquitination and destruction of APOBEC3. Both groups suggest that disrupting the Vif–CBF-β interaction could provide a new therapeutic target against HIV-1 infection. The human APOBEC3 cytidine deaminases are potent inhibitors of diverse retroviruses, including human immunodeficiency virus-1 (HIV-1) 1 , 2 , 3 , 4 , 5 , 6 . HIV-1 Vif forms an E3 ubiquitin ligase complex with cullin 5 (CUL5), elongin B and elongin C 7 , 8 , 9 , which promotes the polyubiquitination and degradation of APOBEC3 substrates 7 , 10 , 11 , 12 , 13 , 14 . Here we demonstrate in human T cells that core binding factor β (CBF-β) is a key regulator of the evasion of HIV-1 from the host defence mediated by APOBEC3. CBF-β, the non-DNA-binding subunit of a heterodimeric transcription factor, regulates the folding and DNA-binding activity of partner RUNX family proteins, which have important roles in the development and differentiation of diverse cell types, including T lymphocytes 15 , 16 . In our study, knockdown of endogenous CBF-β blocked Vif-induced APOBEC3G polyubiquitination and degradation. CBF-β was not required for the interaction between Vif and APOBEC3G, yet was essential for the assembly of the Vif–CUL5 E3-ubiquitin-ligase complex. CBF-β proved to be a unique regulator of primate lentiviral Vif and not a general component of the CUL5 E3 ubiquitin ligase. We show that Vif and CBF-β physically interact, and that the amino-terminal region of Vif is required for this interaction. Furthermore, interactions with Vif required regions in CBF-β that are not involved in RUNX protein binding 17 , 18 , 19 . Considering the importance of the interaction between Vif and CBF-β, disrupting this interaction represents an attractive pharmacological intervention against HIV-1.

The transcriptional control of lineage commitment to various ILC subsets is incompletely understood. Yokoyama and colleagues show that Runx3 is essential for the normal development of ILC1 and ILC3 cells but not ILC2 cells. Subsets of innate lymphoid cells (ILCs) reside in the mucosa and regulate immune responses to external pathogens. While ILCs can be phenotypically classified into ILC1, ILC2 and ILC3 subsets, the transcriptional control of commitment to each ILC lineage is incompletely understood. Here we report that the transcription factor Runx3 was essential for the normal development of ILC1 and ILC3 cells but not of ILC2 cells. Runx3 controlled the survival of ILC1 cells but not of ILC3 cells. Runx3 was required for expression of the transcription factor RORγt and its downstream target, the transcription factor AHR, in ILC3 cells. The absence of Runx3 in ILCs exacerbated infection with Citrobacter rodentium . Therefore, our data establish Runx3 as a key transcription factor in the lineage-specific differentiation of ILC1 and ILC3 cells.

Group 2 innate lymphoid cells (ILC2s) have tissue-resident competence and contribute to the pathogenesis of allergic diseases. However, the mechanisms regulating prolonged ILC2-mediated T H 2 cytokine production under chronic inflammatory conditions are unclear. Here we show that, at homeostasis, Runx deficiency induces excessive ILC2 activation due to overly active GATA-3 functions. By contrast, during allergic inflammation, the absence of Runx impairs the ability of ILC2s to proliferate and produce effector T H 2 cytokines and chemokines. Instead, functional deletion of Runx induces the expression of exhaustion markers, such as IL-10 and TIGIT, on ILC2s. Finally, these ‘exhausted-like’ ILC2s are unable to induce type 2 immune responses to repeated allergen exposures. Thus, Runx confers competence for sustained ILC2 activity at the mucosa, and contributes to allergic pathogenesis. Group 2 innate lymphoid cells (ILC2) are important mediators for allergy, but how ILC2 are regulated under chronic inflammation is still unclear. Here the authors show that Runx transcription factors, which normally suppresses ILC2 activation at steady state, help promote ILC2 activation and type 2 cytokine production in lung allergy mouse models.

HIV-1 Vif recruits host cullin-RING-E3 ubiquitin ligase and CBFβ to degrade the cellular APOBEC3 antiviral proteins through diverse interactions. Recent evidence has shown that Vif also degrades the regulatory subunits PPP2R5(A–E) of cellular protein phosphatase 2A to induce G2/M cell cycle arrest. As PPP2R5 proteins bear no functional or structural resemblance to A3s, it is unclear how Vif can recognize different sets of proteins. Here we report the cryogenic-electron microscopy structure of PPP2R5A in complex with HIV-1 Vif–CBFβ–elongin B–elongin C at 3.58 Å resolution. The structure shows PPP2R5A binds across the Vif molecule, with biochemical and cellular studies confirming a distinct Vif–PPP2R5A interface that partially overlaps with those for A3s. Vif also blocks a canonical PPP2R5A substrate-binding site, indicating that it suppresses the phosphatase activities through both degradation-dependent and degradation-independent mechanisms. Our work identifies critical Vif motifs regulating the recognition of diverse A3 and PPP2R5A substrates, whereby disruption of these host–virus protein interactions could serve as potential targets for HIV-1 therapeutics. The authors solve a cryo-EM structure of the regulatory subunit of human protein phosphatase 2A in complex with HIV-1 Vif-containing E3 ligase, leading to improvement of our understanding of host–virus protein interactions.

RORγt is a key transcription factor regulating both Th17 differentiation and thymocyte development. Although Th17 cells drive autoimmune diseases, inhibiting RORγt to treat autoimmunity also disrupts thymocyte development and can cause lethal thymic lymphoma. We identified a previously unreported RORγt cofactor, CBFβ, and a highly selective RORγt inhibitor, IMU-935, that preferentially disrupt the RORγt-CBFβ interaction in Th17 cells but not thymocytes. This interaction is essential for RORγt function; mice with a RORγt mutant unable to bind CBFβ had impaired Th17 differentiation, were resistant to experimental autoimmune encephalomyelitis (EAE), and had defective thymocyte development. IMU-935 inhibited Th17 differentiation and reduced EAE severity without affecting thymocyte development by selectively targeting the RORγt-CBFβ interaction in Th17 cells but not in thymocytes. This differential effect arose because different concentrations of IMU-935 were required to disrupt the interaction in Th17 cells versus thymocytes, due to varying levels of RUNX1 that compete with RORγt for CBFβ binding. This study reveals an unreported mechanism for RORγt regulation and a selective RORγt inhibitor that prevents Th17-driven autoimmunity without the risk of lethal lymphoma from thymocyte disruption.

The CBFB gene is frequently mutated in several types of solid tumors. Emerging evidence suggests that CBFB is a tumor suppressor in breast cancer. However, our understanding of the tumor suppressive function of CBFB remains incomplete. Here, we analyze genetic interactions between mutations of CBFB and other highly mutated genes in human breast cancer datasets and find that CBFB and TP53 mutations are mutually exclusive, suggesting a functional association between CBFB and p53. Integrated genomic studies reveal that TAp73 is a common transcriptional target of CBFB and p53. CBFB cooperates with p53 to maintain TAp73 expression, as either CBFB or p53 loss leads to TAp73 depletion. TAp73 re-expression abrogates the tumorigenic effect of CBFB deletion. Although TAp73 loss alone is insufficient for tumorigenesis, it enhances the tumorigenic effect of NOTCH3 overexpression, a downstream event of CBFB loss. Immunohistochemistry shows that p73 loss is coupled with higher proliferation in xenografts. Moreover, TAp73 loss-of-expression is a frequent event in human breast cancer tumors and cell lines. Together, our results significantly advance our understanding of the tumor suppressive functions of CBFB and reveal a mechanism underlying the communication between the two tumor suppressors CBFB and p53.

The pathogenesis of cleidocranial dysplasia (CCD) as well as the specific role of core binding factor β (Cbfβ) and the Runt-related transcription factor (RUNX)/Cbfβ complex in postnatal skeletogenesis remain unclear. We demonstrate that Cbfβ ablation in osteoblast precursors, differentiating chondrocytes, osteoblasts, and odontoblasts via Osterix- Cre, results in severe craniofacial dysplasia, skeletal dysplasia, abnormal teeth, and a phenotype recapitulating the clinical features of CCD. Cbfβ ᶠ/ᶠOsterix-Cre mice have fewer proliferative and hypertrophic chondrocytes, fewer osteoblasts, and almost absent trabecular bone, indicating that Cbfβ may maintain trabecular bone formation through its function in hypertrophic chondrocytes and osteoblasts. Cbfβ ᶠ/ᶠCollagen , type 1 , alpha 1 (Col1α1)– Cre mice show decreased bone mineralization and skeletal deformities, but no radical deformities in teeth, mandibles, or cartilage, indicating that osteoblast lineage-specific ablation of Cbfβ results in milder bone defects and less resemblance to CCD. Activating transcription factor 4 (Atf4) and Osterix protein levels in both mutant mice are dramatically reduced. ChIP assays show that Cbfβ directly associates with the promoter regions of Atf4 and Osterix . Our data further demonstrate that Cbfβ highly up-regulates the expression of Atf4 at the transcriptional regulation level. Overall, our genetic dissection approach revealed that Cbfβ plays an indispensable role in postnatal skeletal development and homeostasis in various skeletal cell types, at least partially by up-regulating the expression of Atf4 and Osterix. It also revealed that CCD may result from functional defects of the Runx2/Cbfβ heterodimeric complex in various skeletal cells. These insights into the role of Cbfβ in postnatal skeletogenesis and CCD pathogenesis may assist in the development of new therapies for CCD and osteoporosis.

We report a unique pediatric acute myeloid leukemia (AML) case characterized by a CBFB::MYH11 fusion located on a supernumerary ring chromosome 16. Following diagnosis through comprehensive blood and bone marrow assays, the patient was enrolled in the Children’s Oncology Group (COG) study AAML1831 and randomized to the experimental treatment arm (Arm B). She received induction chemotherapy with CPX-351 (liposomal daunorubicin and cytarabine), gemtuzumab and ozogamicin (GO), and the cardioprotectant dexrazoxane and achieved complete remission (CR). The patient completed the treatment with sustained CR for 18 months. This case represents a rare cytogenetic phenomenon that is not well-documented in the current literature. Through a review of relevant publications, we contextualize this case within the spectrum of core binding factor AML (CBF-AML), highlighting diagnostic approaches, treatment strategies, and prognostic implications, particularly in cases involving atypical CBFB::MYH11 fusions. The durable remission observed in this patient, despite the unusual cytogenetic presentation, provides valuable insights into therapeutic management. This report underscores the cytogenetic and molecular heterogeneity of CBFB::MYH11 AML and emphasizes the importance of comprehensive genetic profiling using advanced techniques such as chromosomal microarray and next-generation sequencing.

Mucosa-associated lymphoid tissue (MALT) is a group of secondary and organized lymphoid tissue that develops at different mucosal surfaces. Peyer's patches (PPs), nasopharynx-associated lymphoid tissue (NALT), and tear duct-associated lymphoid tissue (TALT) are representative MALT in the small intestine, nasal cavity, and lacrimal sac, respectively. A recent study has shown that transcriptional regulators of core binding factor (Cbf) β2 and promotor-1-transcribed Runt-related transcription factor 1 (P1-Runx1) are required for the differentiation of CD3-CD4+CD45+ lymphoid tissue inducer (LTi) cells, which initiate and trigger the developmental program of PPs, but the involvement of this pathway in NALT and TALT development remains to be elucidated. Here we report that Cbfβ2 plays an essential role in NALT and TALT development by regulating LTi cell trafficking to the NALT and TALT anlagens. Cbfβ2 was expressed in LTi cells in all three types of MALT examined. Indeed, similar to the previous finding for PPs, we found that Cbfβ2-/- mice lacked NALT and TALT lymphoid structures. However, in contrast to PPs, NALT and TALT developed normally in the absence of P1-Runx1 or other Runx family members such as Runx2 and Runx3. LTi cells for NALT and TALT differentiated normally but did not accumulate in the respective lymphoid tissue anlagens in Cbfβ2-/- mice. These findings demonstrate that Cbfβ2 is a central regulator of the MALT developmental program, but the dependency of Runx proteins on the lymphoid tissue development would differ among PPs, NALT, and TALT.

The transcription factor IRF8 is essential for the development of monocytes and dendritic cells (DCs), whereas it inhibits neutrophilic differentiation. It is unclear how Irf8 expression is regulated and how this single transcription factor supports the generation of both monocytes and DCs. Here, we identified a RUNX–CBFβ-driven enhancer 56 kb downstream of the Irf8 transcription start site. Deletion of this enhancer in vivo significantly decreased Irf8 expression throughout the myeloid lineage from the progenitor stages, thus resulting in loss of common DC progenitors and overproduction of Ly6C + monocytes. We demonstrated that high, low or null expression of IRF8 in hematopoietic progenitor cells promotes differentiation toward type 1 conventional DCs, Ly6C + monocytes or neutrophils, respectively, via epigenetic regulation of distinct sets of enhancers in cooperation with other transcription factors. Our results illustrate the mechanism through which IRF8 controls the lineage choice in a dose-dependent manner within the myeloid cell system. The transcription factor IRF8 is required for both DC and monocyte differentiation from common myeloid progenitors. Tamura and colleagues identify an enhancer (+56 kb) in the Irf8 locus that regulates early myeloid lineage choice.