Effective and sustained inhibition of non-enzymatic oncogenic driver proteins represents a major pharmacologic challenge. The clinical success of thalidomide analogs demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets 1 – 3 , but a significant subset of proteins are recalcitrant to targeted protein degradation using current approaches 4 , 5 . Here we report an alternative mechanism, whereby a small molecule induces highly specific, reversible polymerization, sequestration into cellular foci, and subsequent degradation of a target protein. BI-3802 is a small molecule that binds the BTB domain of the oncogenic transcription factor BCL6 and results in proteasomal degradation 6 . We used cryo-EM to reveal how the solvent-exposed moiety of a BCL6 inhibitor contributes to a composite ligand/protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to superior pharmacological activity. These findings create new avenues for the development of therapeutics and synthetic biology.

Background Wolbachia inherited intracellular bacteria can manipulate the reproduction of their insect hosts through cytoplasmic incompatibility (CI), and certain strains have also been shown to inhibit the replication or dissemination of viruses. Wolbachia strains also vary in their relative fitness effects on their hosts and this is a particularly important consideration with respect to the potential of newly created transinfections for use in disease control.Methodology/Principal FindingsIn Aedes albopictus mosquitoes transinfected with the wMel strain from Drosophila melanogaster, which we previously reported to be unable to transmit dengue in lab challenges, no significant detrimental effects were observed on egg hatch rate, fecundity, adult longevity or male mating competitiveness. All these parameters influence the population dynamics of Wolbachia, and the data presented are favourable with respect to the aim of taking wMel to high population frequency. Challenge with the chikungunya (CHIKV) virus, for which Ae. albopictus is an important vector, was conducted and the presence of wMel abolished CHIKV dissemination to the saliva.Conclusions/significanceTaken together, these data suggest that introducing wMel into natural Ae. albopictus populations using bidirectional CI could be an efficient strategy for preventing or reducing the transmission of arboviruses by this species.

Hematopoietic ageing involves declining erythropoiesis and lymphopoiesis, leading to frequent anaemia and decreased adaptive immunity. How intrinsic changes to the hematopoietic stem cells (HSCs), an altered microenvironment and systemic factors contribute to this process is not fully understood. Here we use bone marrow stromal cells as sensors of age-associated changes to the bone marrow microenvironment, and observe up-regulation of IL-6 and TGFβ signalling-induced gene expression in aged bone marrow stroma. Inhibition of TGFβ signalling leads to reversal of age-associated HSC platelet lineage bias, increased generation of lymphoid progenitors and rebalanced HSC lineage output in transplantation assays. In contrast, decreased erythropoiesis is not an intrinsic property of aged HSCs, but associated with decreased levels and functionality of erythroid progenitor populations, defects ameliorated by TGFβ-receptor and IL-6 inhibition, respectively. These results show that both HSC-intrinsic and-extrinsic mechanisms are involved in age-associated hematopoietic decline, and identify therapeutic targets that promote their reversal.

No abstract

Flt3 expression is absent in the large majority of phenotypic hematopoietic stem cells (HSCs). Mead et al. show that FLT3-ITD–driven myeloproliferation causes cell-extrinsic suppression of the normal HSC reservoir through disruption of HSC-supporting BM stromal cells, including overexpression of TNF.

SummaryWhole exome sequencing was performed in a patient with myelodysplastic syndrome before and after progression to acute myeloid leukaemia. Mutations in several genes, including SETBP1, were identified following leukaemic transformation. Screening of 328 patients with myeloid disorders revealed SETBP1 mutations in 14 patients (4Á3%), 7 of whom had À7/del(7q) and 3 had i(17)(q10), cytogenetic markers associated with shortened overall survival and increased risk of leukaemic evolution. SETBP1 mutations were frequently acquired at the time of leukaemic evolution, coinciding with increase of leukaemic blasts. These data suggest that SET-BP1 mutations may play a role in MDS and chronic myelomonocytic leukaemia disease progression.

Highlights d Biallelic C/EBPa and GATA-2 ZnF1 mutations synergize during leukemogenesis d GATA-2 ZnF1 mutation generates an erythroid-permissive chromatin state d C/EBPa and GATA-2 mutant NMPs show ectopic erythroid lineage potential d Transformed leukemic NMPs are bipotent neutrophilerythroid leukemia-initiating cells

Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. This finding of mutation-synergy is broadly applicable other mutations that activate the JAK/STAT pathway or disrupt CEBPA function (i.e. activating mutations in JAK3 and Core Binding Factor translocations). The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation, confirming predictions from clinical sequencing data. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity. B.J.D.