Activated B-cell-like (ABC) and germinal center B-cell-like diffuse large B-cell lymphoma (DLBCL) represent the 2 major molecular DLBCL subtypes. They are characterized by differences in clinical course and by divergent addiction to oncogenic pathways. To determine activity of novel compounds in these 2 subtypes, we conducted an unbiased pharmacologic in vitro screen. The phosphatidylinositol-3-kinase (PI3K) α/δ (PI3Kα/δ) inhibitor AZD8835 showed marked potency in ABC DLBCL models, whereas the protein kinase B (AKT) inhibitor AZD5363 induced apoptosis in PTEN-deficient DLBCLs irrespective of their molecular subtype. These in vitro results were confirmed in various cell line xenograft and patient-derived xenograft mouse models in vivo. Treatment with AZD8835 induced inhibition of nuclear factor κB signaling, prompting us to combine AZD8835 with the Bruton’s tyrosine kinase inhibitor ibrutinib. This combination was synergistic and effective both in vitro and in vivo. In contrast, the AKT inhibitor AZD5363 was effective in PTEN-deficient DLBCLs through downregulation of the oncogenic transcription factor MYC. Collectively, our data suggest that patients should be stratified according to their oncogenic dependencies when treated with PI3K and AKT inhibitors. Publisher9s Note: There is an Inside Blood Commentary on this article in this issue. Key Points PI3Kα/δ inhibition induces cytotoxicity in ABC DLBCLs through downregulation of NF-κB signaling. Inhibition of AKT induces cytotoxicity by downregulation of MYC in PTEN-deficient DLBCL models in vivo and in vitro.

Projectile angular-differential cross sections for single-transfer and transfer excitation have been calculated with the two-center extension of the nonperturbative basis generator method for 5–200 keV proton-helium collisions. The calculations are based on the independent electron model, and the eikonal approximation has been used to extract angular-differential cross sections from impact-parameter-dependent transition amplitudes. The present results are compared with experimental and previous theoretical data where available. In particular, we consider the ratio of transfer excitation to single capture versus double excitation to single excitation at intermediate energies. An experimentally observed structure in this ratio at a scattering angle about 0.5 mrad is qualitatively reproduced, while a previous classical evaluation failed in this respect. Therefore, we conclude that this structure is caused by quantum mechanical heavy-particle-electron couplings.

The electron dynamics in $p\text{-He}$ and ${\text{He}}^{2+}\text{-He}$ collisions have been investigated on the level of the independent electron model by using the two-center basis generator method. Projectile angular-differential cross sections for various one- and two-electron processes involving electron transfer have been calculated with the eikonal approximation. Overall, the calculated cross sections are in good agreement with the most recent experimental cold target recoil ion momentum spectroscopy data taken at impact energies in the range from 40 to 630 keV/amu. This demonstrates, somewhat surprisingly, that electron correlations play but a minor role for the processes and the energies considered.

We have performed a kinematically complete experiment on transfer excitation in intermediate-energy proton-helium collisions. The differential cross sections were compared to double excitation data and a nonperturbative time-dependent calculation. This comparison reveals the importance of dynamic couplings between the motion of the heavy nuclei and electronic transitions and/or electron-electron correlation effects.

Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late-stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Upon cell-specific deletion of C/EBPβ in CD11c⁺MHCII^hi DCs, gene expression profiles of splenic C/EBPβ^−/− DCs showed a down-regulation of E2F cell cycle target genes and associated proliferation signaling pathways, whereas maturation signatures were enriched. Total splenic DC cell numbers were modestly increased but differentiation into cDC1 and cDC2 subsets were unaltered. The splenic CD11c⁺MHCII^hiCD64⁺ DC compartment was also increased, suggesting that C/EBPβ deficiency favors the expansion of monocytic-derived DCs. Expression of C/EBPβ could be mimicked in LAP/LAP* isoform knockin DCs, whereas the short isoform LIP supported a differentiation program similar to deletion of the full-length TF. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ^−/− bone marrow-derived DCs matured much faster enabling them to activate and polarize T cells stronger. In contrast to a homeostatic condition, lymphoma-exposed DCs exhibited an up-regulation of the E2F transcriptional pathways and an impaired maturation. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their protumorigenic function in primary B cell lymphoma cocultures. Thus, C/EBPβ plays a unique role in DC maturation and immunostimulatory functionality and emerges as a key factor of the tumor microenvironment that promotes lymphomagenesis. Significance Complex transcription factor networks regulate the development, maturation, and lineage commitment of dendritic cell (DC) subsets. Here, we demonstrate a previously unexpected role of the transcription factor C/EBPβ in murine DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Regulated expression of functional C/EBPβ isoforms enables a controlled maturation of DCs. In contrast, the presence of lymphoma cells leads to an up-regulation of C/EBPβ in DCs which transforms them into an immature and protumorigenic subtype. This study also shows that inhibition of the C/EBPβ/mTOR signaling axis abrogates the protumorigenic function of human DCs, suggesting that inhibitors regulating C/EBPβ activity can be used for blocking tumor-promoting functions of DCs in the treatment of hematological neoplasms.