ROS-dependent S-palmitoylation activates cleaved and intact gasdermin D.

Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation and was previously shown to form large transmembrane pores after cleavage by inflammatory caspases to generate the GSDMD N-terminal domain (GSDMD-NT)1-10. Here we report that GSDMD Cys191 is S-palmitoylated and that palmitoylation is required for pore formation. S-palmitoylation, which does not affect GSDMD cleavage, is augmented by mitochondria-generated reactive oxygen species (ROS). Cleavage-deficient GSDMD (D275A) is also palmitoylated after inflammasome stimulation or treatment with ROS activators and causes pyroptosis, although less efficiently than palmitoylated GSDMD-NT. Palmitoylated, but not unpalmitoylated, full-length GSDMD induces liposome leakage and forms a pore similar in structure to GSDMD-NT pores shown by cryogenic electron microscopy. ZDHHC5 and ZDHHC9 are the major palmitoyltransferases that mediate GSDMD palmitoylation, and their expression is upregulated by inflammasome activation and ROS. The other human gasdermins are also palmitoylated at their N termini. These data challenge the concept that cleavage is the only trigger for GSDMD activation. They suggest that reversible palmitoylation is a checkpoint for pore formation by both GSDMD-NT and intact GSDMD that functions as a general switch for the activation of this pore-forming family.

NINJ1 mediates plasma membrane rupture by cutting and releasing membrane disks.

The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (⍺1, ⍺2) and transmembrane (TM) helices (⍺3, ⍺4) and forms a chain of subunits, mainly by the TM helices and ⍺1. ⍺3 and ⍺4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by ⍺1 and ⍺2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.

ROS-dependent palmitoylation is an obligate licensing modification for GSDMD pore formation.

Gasdermin D (GSDMD) is the common effector for cytokine secretion and pyroptosis downstream of inflammasome activation by forming large transmembrane pores upon cleavage by inflammatory caspases. Here we report the surprising finding that GSDMD cleavage is not sufficient for its pore formation. Instead, GSDMD is lipidated by S-palmitoylation at Cys191 upon inflammasome activation, and only palmitoylated GSDMD N-terminal domain (GSDMD-NT) is capable of membrane translocation and pore formation, suggesting that palmitoylation licenses GSDMD activation. Treatment by the palmitoylation inhibitor 2-bromopalmitate and alanine mutation of Cys191 abrogate GSDMD membrane localization, cytokine secretion, and cell death, without affecting GSDMD cleavage. Because palmitoylation is formed by a reversible thioester bond sensitive to free thiols, we tested if GSDMD palmitoylation is regulated by cellular redox state. Lipopolysaccharide (LPS) mildly and LPS plus the NLRP3 inflammasome activator nigericin markedly elevate reactive oxygen species (ROS) and GSDMD palmitoylation, suggesting that these two processes are coupled. Manipulation of cellular ROS by its activators and quenchers augment and abolish, respectively, GSDMD palmitoylation, GSDMD pore formation and cell death. We discover that zDHHC5 and zDHHC9 are the major palmitoyl transferases that mediate GSDMD palmitoylation, and when cleaved, recombinant and partly palmitoylated GSDMD is 10-fold more active in pore formation than bacterially expressed, unpalmitoylated GSDMD, evidenced by liposome leakage assay. Finally, other GSDM family members are also palmitoylated, suggesting that ROS stress and palmitoylation may be a general switch for the activation of this pore-forming family. One-Sentence Summary: GSDMD palmitoylation is induced by ROS and required for pore formation.

Piezo mechanosensory channels regulate centrosome integrity and mitotic entry.

Piezo1 and 2 are evolutionarily conserved mechanosensory cation channels known to function on the cell surface by responding to external pressure and transducing a mechanically activated Ca2+ current. Here we show that both Piezo1 and 2 also exhibit concentrated intracellular localization at centrosomes. Both Piezo1 and 2 loss-of-function and Piezo1 activation by the small molecule Yoda1 result in supernumerary centrosomes, premature centriole disengagement, multi-polar spindles, and mitotic delay. By using a GFP, Calmodulin and M13 Protein fusion (GCaMP) Ca2+-sensitive reporter, we show that perturbations in Piezo modulate Ca2+ flux at centrosomes. Moreover, the inhibition of Polo-like-kinase 1 eliminates Yoda1-induced centriole disengagement. Because previous studies have implicated force generation by microtubules as essential for maintaining centrosomal integrity, we propose that mechanotransduction by Piezo maintains pericentrosomal Ca2+ within a defined range, possibly through sensing cell intrinsic forces from microtubules.

BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL.

Activated B cell-like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11-BCL10-MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes. SIGNIFICANCE: ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure-function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs. See related commentary by Phelan and Oellerich, p. 1844. This article is highlighted in the In This Issue feature, p. 1825.

[ANTERIOR CUTANEOUS NERVE ENTRAPMENT SYNDROME IN THE ABDOMINAL WALL].

INTRODUCTION: Anterior cutaneous nerve entrapment syndrome (ACNES) is one of the causes of chronic abdominal pain. Symptoms include intense focused chronic abdominal pain, affected by posture changes and exertion. Particularly noticeable are the lack of pathological findings in laboratory and imaging tests, from the most basic to the more advanced. Proper diagnosis and appropriate treatment depend on raising the clinical suspicion with typical findings on physical examination. Confirmation of the diagnosis is obtained by significant alleviation of pain following injection of local anesthetics into the maximal tender point. Acceptable treatment includes local injections (local anesthetics and occasionally corticosteroids), radiofrequency neurotomy and, if failed, surgery. Accurate diagnosis and proper treatment result in pain relief in most patients.

Spontaneous labor patterns among women attempting vaginal birth after cesarean delivery.

OBJECTIVE: This study evaluated spontaneous labor patterns among women achieving a vaginal birth after cesarean (VBAC), without a previous vaginal delivery in relation to nulliparous women. METHODS: This historical cohort study included 422 women attempting VBAC and 150 nulliparas. We examined time intervals for each centimeter of cervical dilation and compared labor progression in 321 women who achieved spontaneous VBAC and 147 nulliparous women achieving a spontaneous vaginal delivery. Epidural anesthesia use, delivery mode, cord arterial pH and 5-minute Apgar score were also compared. FINDINGS: Women in the VBAC group compared to nulliparous women had similar durations of first (4-10 cm: 4:22 (00:54-13:10) h vs. 4:47 (1:10-15:10) h, p = .61), second (1:07 (8:00-3:21), vs. 1:34 (10:00-3:40), p = .124) and third stages of labor (10:00 (2:00-22:00) vs. 08:00 (3:24-22:12), p = .788). When comparing women who had epidural analgesia to those who did not, no differences were found between the groups regarding durations of first and second stages of labor. Interestingly, among parturients without epidural anesthesia only, the VBAC group had shorter second stage compared to the nulliparous (00:19 (0:04-1:59) vs. 00:47 (0:08-2:09), p = .023). CONCLUSION: Labor patterns among women achieving spontaneous VBAC are similar to those of nulliparous women with spontaneous vaginal deliveries.

Can Social Support on Facebook Influence Fertility Outcomes?

Social support is known to reduce stress and increase quality of life among patients undergoing IVF. Increasing social media use introduces a social support mechanism, yet data regarding the effect of this support on IVF outcomes are scarce. This observational, retrospective cohort study included women undergoing their first IVF cycle at an academic tertiary medical center. Fertility outcomes were compared between 82 women who were active users of social media (posting on Facebook at least 3 times a week) and 83 women who did not use Facebook or any other social media platform (the control group). For the social media group, we coded all Facebook Feed activities (Posts, Comments, Likes) for each participant up to 8 weeks prior to beta hCG test. Social support was measured by average Likes and Comments per post, on fertility outcomes. The social media group included more single women than the control group (17% vs. 5%, respectively, p = 0.012) and had a shorter infertility duration (1.6 ± 0.9 years vs. 2.3 ± 1.4, respectively, p = 0.001(. We found a trend in fertilization rates between groups (social media group 58% vs. controls 50%, p = 0.07). No difference was found regarding pregnancy rate between groups (p = 0.587). The social media group had a lower miscarriage rate compared to the controls (6% vs. 25%, p = 0.042). These results were also validated in the multivariant regression analysis. Social support (via Facebook) may have a positive effect on IVF outcomes, especially regarding miscarriages rate, with minor effect regrading fertilization rate and no effect regarding pregnancy rate. Therefore, encouraging women to be active on Facebook during treatment, including OPU day, may impact treatment results.

NLRP3 cages revealed by full-length mouse NLRP3 structure control pathway activation.

The NACHT-, leucine-rich-repeat- (LRR), and pyrin domain-containing protein 3 (NLRP3) is emerging to be a critical intracellular inflammasome sensor of membrane integrity and a highly important clinical target against chronic inflammation. Here, we report that an endogenous, stimulus-responsive form of full-length mouse NLRP3 is a 12- to 16-mer double-ring cage held together by LRR-LRR interactions with the pyrin domains shielded within the assembly to avoid premature activation. Surprisingly, this NLRP3 form is predominantly membrane localized, which is consistent with previously noted localization of NLRP3 at various membrane organelles. Structure-guided mutagenesis reveals that trans-Golgi network dispersion into vesicles, an early event observed for many NLRP3-activating stimuli, requires the double-ring cages of NLRP3. Double-ring-defective NLRP3 mutants abolish inflammasome punctum formation, caspase-1 processing, and cell death. Thus, our data uncover a physiological NLRP3 oligomer on the membrane that is poised to sense diverse signals to induce inflammasome activation.

[ILIOHYPOGASTRIC NERVE ENTRAPMENT IN A CHILD - A RARE CAUSE FOR CHRONIC ABDOMINAL AND PELVIC PAIN IN CHILDREN].

INTRODUCTION: Entrapment of the iliohypogastric nerve is a rare cause of abdominal pain in children. We present a case report of a 12 year old girl with abdominal pain following a fall accompanied by nausea, vomiting and odynuria. Thorough investigation was normal and a non-organic cause was proposed. With no lasting improvement after local analgesic infiltration, a surgical attempt to disconnect sensory innervation was conducted but pain continued. A second surgical exploration was performed. A tear of the external oblique aponeurosis was found, entrapping terminal branches of the iliohypogastric nerve. A complete clinical resolution followed resection of the nerve and repair of the aponeurosis tear. Entrapment of abdominal cutaneous nerves should be considered in cases with chronic abdominal pain accompanied by localized tenderness and various visceral complaints. Normal laboratory and imaging findings are typical.

Intrahepatic cholestasis of pregnancy: machine-learning algorithm to predict elevated bile acid based on clinical and laboratory data.

PURPOSE: Applying machine-learning models to clinical and laboratory features of women with intrahepatic cholestasis of pregnancy (ICP) and creating algorithm to identify these patients without bile acid measurements. METHODS: This retrospective study included 336 pregnant women with a chief complaint of pruritis without rash during the second/third trimesters. Data extracted included: demographics, obstetric, clinical and laboratory features. The primary outcome was an elevated bile acid measurement ≥ 10 µmol/L, regardless of liver enzyme levels. We used different machine-learning models and statistical regression to predict elevated bile acid levels. RESULTS: Among 336 women who complained about pruritis, 167 had bile acids ≥ 10 µmol/L and 169 had normal levels. Women with elevated bile acids were older than those with normal levels (p = 0.001), higher parity (p = 0.001), and higher glutamic oxaloacetic transaminase ( GOT) (p = 0.001) and glutamic-pyruvic transaminase (GPT) levels (p = 0.001). Using machine-learning models, the XGB Classifier model was the most accurate (area under the curve (AUC), 0.9) followed by the K-neighbors model (AUC, 0.86); and then the Support Vector Classification (SVC) model (AUC, 0.82). The model with the lowest predicative ability was the logistic regression (AUC, 0.72). The maximum sensitivity of the XGB model was 86% and specificity 75%. The best predictive parameters of the XGB model were elevated GOT (Importance 0.17), elevated GPT (Importance 0.16), family history of bile disease (0.16) and previous pregnancy with ICP (0.13). CONCLUSION: Machine-learning models using clinical data may predict ICP more accurately than logistic regression does. Using detection algorithms derived from these techniques may improve identification of ICP, especially when bile acid testing is not available.

Mechanism of filament formation in UPA-promoted CARD8 and NLRP1 inflammasomes.

NLRP1 and CARD8 are related cytosolic sensors that upon activation form supramolecular signalling complexes known as canonical inflammasomes, resulting in caspase-1 activation, cytokine maturation and/or pyroptotic cell death. NLRP1 and CARD8 use their C-terminal (CT) fragments containing a caspase recruitment domain (CARD) and the UPA (conserved in UNC5, PIDD, and ankyrins) subdomain for self-oligomerization, which in turn form the platform to recruit the inflammasome adaptor ASC (apoptosis-associated speck-like protein containing a CARD) or caspase-1, respectively. Here, we report cryo-EM structures of NLRP1-CT and CARD8-CT assemblies, in which the respective CARDs form central helical filaments that are promoted by oligomerized, but flexibly linked, UPAs surrounding the filaments. Through biochemical and cellular approaches, we demonstrate that the UPA itself reduces the threshold needed for NLRP1-CT and CARD8-CT filament formation and signalling. Structural analyses provide insights on the mode of ASC recruitment by NLRP1-CT and the contrasting direct recruitment of caspase-1 by CARD8-CT. We also discover that subunits in the central NLRP1CARD filament dimerize with additional exterior CARDs, which roughly doubles its thickness and is unique among all known CARD filaments. Finally, we engineer and determine the structure of an ASCCARD-caspase-1CARD octamer, which suggests that ASC uses opposing surfaces for NLRP1, versus caspase-1, recruitment. Together these structures capture the architecture and specificity of the active NLRP1 and CARD8 inflammasomes in addition to key heteromeric CARD-CARD interactions governing inflammasome signalling.

Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization.

BAX is a pro-apoptotic protein that transforms from a cytosolic monomer into a toxic oligomer that permeabilizes the mitochondrial outer membrane. How BAX monomers assemble into a higher-order conformation, and the structural determinants essential to membrane permeabilization, remain a mechanistic mystery. A key hurdle has been the inability to generate a homogeneous BAX oligomer (BAXO) for analysis. Here, we report the production and characterization of a full-length BAXO that recapitulates physiologic BAX activation. Multidisciplinary studies revealed striking conformational consequences of oligomerization and insight into the macromolecular structure of oligomeric BAX. Importantly, BAXO enabled the assignment of specific roles to particular residues and α helices that mediate individual steps of the BAX activation pathway, including unexpected functionalities of BAX α6 and α9 in driving membrane disruption. Our results provide the first glimpse of a full-length and functional BAXO, revealing structural requirements for the elusive execution phase of mitochondrial apoptosis.

Gain-of-function mutations in CARD11 promote enhanced aggregation and idiosyncratic signalosome assembly.

BENTA (B cell Expansion with NF-κB and T cell Anergy) is a novel lymphoproliferative disorder caused by germline, gain-of-function (GOF) mutations in the lymphocyte-restricted scaffolding protein CARD11. Similar somatic CARD11 mutations are found in lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL). Normally, antigen receptor (AgR) engagement converts CARD11 into an active conformation that nucleates a signalosome required for IκB kinase (IKK) activation and NF-κB nuclear translocation. However, GOF CARD11 mutants drive constitutive NF-κB activity without AgR stimulation. Here we show that unlike wild-type CARD11, GOF CARD11 mutants can form large, peculiar cytosolic protein aggregates we term mCADS (mutant CARD11 dependent shells). MALT1 and phospho-IKK are reliably colocalized with mCADS, indicative of active signaling. Moreover, endogenous mCADS are detectable in ABC-DLBCL lines harboring similar GOF CARD11 mutations. The unique aggregation potential of GOF CARD11 mutants may represent a novel therapeutic target for treating BENTA or DLBCL.

The temporal effect of Category II fetal monitoring on neonatal outcomes.

OBJECTIVE: To correlate the duration of Category II cardiotocograms (CTG) with adverse neonatal outcomes associated with perinatal asphyxia and determine the duration before fetal compromise. STUDY DESIGN: This retrospective, observational study used electronic medical record data from a cohort of 271 patients, delivered by C-section due to non-reassuring fetal heart rate, at a tertiary medical center, from 2015 through 2017. Duration of Category II CTG, variability, tachycardia and deceleration frequency were analyzed and correlated to immediate postnatal outcomes. including cord pH ≤ 7, cord base excess >12, 1- and 5-min Apgar scores ≤7, need for ventilation, need for chest compressions, NICU admission, hypoglycemia and convulsions. Intrapartum fever and meconium stained amniotic fluid were correlated to the same outcomes. Categorical and continuous variables were analyzed using chi-square and t-tests, respectively. P < 0.05 was considered significant. RESULTS: The mean duration of Category II CTG was 146 min (range 17-553). Longer duration did not result in increased rates of adverse neonatal outcomes. In contrast, reduced fetal heart rate (FHR) variability, fetal tachycardia and intrapartum fever did show increased rates of adverse neonatal outcomes, as follows: patients exhibiting reduced vs. normal (FHR) variability had 12.9% vs. 1.4% cord pH ≤ 7, P = 0.006 and 12.5% vs. 1.3% cord BE > 12, P = 0.004: patients with fetal tachycardia vs. normal baseline FHR exhibited 48% vs. 17.9% 1-minute Apgar score ≤7, P = 0.0004; 8% vs. 0.8% 5-minute Apgar score ≤7, P = 0.04; and 48% vs. 18.7% ventilation support, P < 0.001; patients with intrapartum fever vs. normal temperature, cord BE > 12 was seen in 9.7% vs. 1.7%, P = 0.035; 1-minute Apgar score was ≤7 in 35.5% vs. 18.7%, P = 0.03; 5-minute Apgar score ≤7 in 9.7% vs. 0.4%, P = 0.005; need for ventilation in 35.5% vs. 19.6%, P = 0.042; need for chest compressions in 6.45% vs. none, P = 0.013; and NICU admission in 12.9% vs. 2.5%, P = 0.018. CONCLUSIONS: Our results suggest that the duration of Category II CTG alone does not appear to predict perinatal asphyxia. Parameters associated with perinatal asphyxia are reduced FHR variability, fetal tachycardia and intrapartum fever. Therefore, when contemplating intervention during labor to avoid fetal asphyxia, these parameters should be strongly considered.

Assembly mechanism of the CARMA1-BCL10-MALT1-TRAF6 signalosome.

The CARMA1-BCL10-MALT1 (CBM) signalosome is a central mediator of T cell receptor and B cell receptor-induced NF-κB signaling that regulates multiple lymphocyte functions. While caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1 (CARMA1) nucleates B cell lymphoma 10 (BCL10) filament formation through interactions between CARDs, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a paracaspase with structural similarity to caspases, which recruits TNF receptor-associated factor 6 (TRAF6) for K63-linked polyubiquitination. Here we present cryo-electron microscopy (cryo-EM) structure of the BCL10 CARD filament at 4.0-Å resolution. The structure redefines CARD-CARD interactions compared with the previous EM structure determined from a negatively stained sample. Surprisingly, time-lapse confocal imaging shows that BCL10 polymerizes in a unidirectional manner. CARMA1, the BCL10 nucleator, serves as a hub for formation of star-shaped filamentous networks of BCL10 and significantly decreases the lag period of BCL10 polymerization. Cooperative MALT1 interaction with BCL10 filaments observed under EM suggests immediate dimerization of MALT1 in the BCL10 filamentous scaffold. In addition, TRAF6 cooperatively decorates CBM filaments to form higher-order assemblies, likely resulting in all-or-none activation of the downstream pathway. Collectively, these data reveal biophysical mechanisms in the assembly of the CARMA1-BCL10-MALT1-TRAF6 complex for signal transduction.

Cryo-EM structure of the activated NAIP2-NLRC4 inflammasome reveals nucleated polymerization.

The NLR family apoptosis inhibitory proteins (NAIPs) bind conserved bacterial ligands, such as the bacterial rod protein PrgJ, and recruit NLR family CARD-containing protein 4 (NLRC4) as the inflammasome adapter to activate innate immunity. We found that the PrgJ-NAIP2-NLRC4 inflammasome is assembled into multisubunit disk-like structures through a unidirectional adenosine triphosphatase polymerization, primed with a single PrgJ-activated NAIP2 per disk. Cryo-electron microscopy (cryo-EM) reconstruction at subnanometer resolution revealed a ~90° hinge rotation accompanying NLRC4 activation. Unlike in the related heptameric Apaf-1 apoptosome, in which each subunit needs to be conformationally activated by its ligand before assembly, a single PrgJ-activated NAIP2 initiates NLRC4 polymerization in a domino-like reaction to promote the disk assembly. These insights reveal the mechanism of signal amplification in NAIP-NLRC4 inflammasomes.

Room temperature biological quantum random walk in phycocyanin nanowires.

Quantum nano-structures are likely to become primary elements of future devices. However, there are a number of significant scientific challenges to real world applications of quantum devices. These include de-coherence that erodes operation of a quantum device and control issues. In nature, certain processes have been shown to use quantum mechanical processes for overcoming these barriers. One well-known example is the high energy transmission efficiency of photosynthetic light harvesting complexes. Utilizing such systems for fabricating nano-devices provides a new approach to creating self-assembled nano-energy guides. In this study, we use isolated phycocyanin (PC) proteins that can self-assemble into bundles of nanowires. We show two methods for controlling the organization of the bundles. These nanowires exhibit long range quantum energy transfer through hundreds of proteins. Such results provide new efficient building blocks for coupling to nano-devices, and shed light on distribution and the efficiency of energy transfer mechanisms in biological systems and its quantum nature.

The CBM signalosome: potential therapeutic target for aggressive lymphoma?

The CBM signalosome plays a pivotal role in mediating antigen-receptor induced NF-κB signaling to regulate lymphocyte functions. The CBM complex forms filamentous structure and recruits downstream signaling components to activate NF-κB. MALT1, the protease component in the CBM complex, cleaves key proteins in the feedback loop of the NF-κB signaling pathway and enhances NF-κB activation. The aberrant activity of the CBM complex has been linked to aggressive lymphoma. Recent years have witnessed dramatic progresses in understanding the assembly mechanism of the CBM complex, and advances in the development of targeted therapy for aggressive lymphoma. Here, we will highlight these progresses and give an outlook on the potential translation of this knowledge from bench to bedside for aggressive lymphoma patients.