Specific antibodies to Anopheles gSG6-P1 salivary peptide to assess early childhood exposure to malaria vector bites.

BACKGROUND: The estimates of risk of malaria in early childhood are imprecise given the current entomologic and parasitological tools. Thus, the utility of anti-Anopheles salivary gSG6-P1 peptide antibody responses in measuring exposure to Anopheles bites during early infancy has been assessed. METHODS: Anti-gSG6-P1 IgG and IgM levels were evaluated in 133 infants (in Benin) at three (M3), six (M6), nine (M9) and 12 (M12) months of age. Specific IgG levels were also assessed in their respective umbilical cord blood (IUCB) and maternal blood (MPB). RESULTS: At M3, 93.98 and 41.35% of infants had anti-gSG6-P1 IgG and IgM Ab, respectively. Specific median IgG and IgM levels gradually increased between M3 and M6 (p < 0.0001 and p < 0.001), M6-M9 (p < 0.0001 and p = 0.085) and M9-M12 (p = 0.002 and p = 0.03). These levels were positively associated with the Plasmodium falciparum infection intensity (p = 0.006 and 0.003), and inversely with the use of insecticide-treated bed nets (p = 0.003 and 0.3). Levels of specific IgG in the MPB were positively correlated to those in the IUCB (R = 0.73; p < 0.0001) and those at M3 (R = 0.34; p < 0.0001). CONCLUSION: The exposure level to Anopheles bites, and then the risk of malaria infection, can be evaluated in young infants by assessing anti-gSG6-P1 IgM and IgG responses before and after 6-months of age, respectively. This tool can be useful in epidemiological evaluation and surveillance of malaria risk during the first year of life.

Pivotal role of the endoplasmic reticulum stress-related XBP1s/miR-22/SIRT1 axis in acute myeloid leukemia apoptosis and response to chemotherapy.

Malignant growth relies on rapid protein synthesis frequently leading to endoplasmic reticulum (ER) overload and accumulation of unfolded or misfolded protein in this cellular compartment. In the ER, protein homeostasis is finely regulated by a mechanism called the unfolded protein response (UPR), involving the activation of signalization pathways mediated by three transmembrane proteins, namely PERK, IRE1 and ATF6. IRE1 endoribonuclease activation leads in particular to the splicing of the cytosolic mRNA encoding the key UPR-specific transcription factor XBP1s. Our study shows that sustained activation of XBP1s expression in acute myeloid leukemia (AML) cells induces apoptosis in vitro and in vivo, whereas a moderate XBP1s expression sensitizes cells to chemotherapeutic treatments. ChIP-seq experiments identified specific XBP1s target genes including the MIR22HG lncRNA, the precursor transcript of microRNA-22-3p. miR-22-3p upregulation by XBP1s or forced expression of miR-22 significantly decreases cell's viability and sensitizes leukemic cells to chemotherapy. We found that miR-22-3p intracellular effects result at least partially from the targeting of the mRNA encoding the deacetylase sirtuin-1 (SIRT1), a well-established pro-survival factor. Therefore, this novel XBP1s/miR-22/SIRT1 axis identified could play a pivotal role in the proliferation and chemotherapeutic response of leukemic cells.

High Levels of miR-7-5p Potentiate Crizotinib-Induced Cytokilling and Autophagic Flux by Targeting RAF1 in NPM-ALK Positive Lymphoma Cells.

Anaplastic lymphoma kinase positive anaplastic large cell lymphomas (ALK+ ALCL) are an aggressive pediatric disease. The therapeutic options comprise chemotherapy, which is efficient in approximately 70% of patients, and targeted therapies, such as crizotinib (an ALK tyrosine kinase inhibitor (TKI)), used in refractory/relapsed cases. Research efforts have also converged toward the development of combined therapies to improve treatment. In this context, we studied whether autophagy could be modulated to improve crizotinib therapy. Autophagy is a vesicular recycling pathway, known to be associated with either cell survival or cell death depending on the cancer and therapy. We previously demonstrated that crizotinib induced cytoprotective autophagy in ALK+ lymphoma cells and that its further intensification was associated with cell death. In line with these results, we show here that combined ALK and Rapidly Accelerated Fibrosarcoma 1 (RAF1) inhibition, using pharmacological (vemurafenib) or molecular (small interfering RNA targeting RAF1 (siRAF1) or microRNA-7-5p (miR-7-5p) mimics) strategies, also triggered autophagy and potentiated the toxicity of TKI. Mechanistically, we found that this combined therapy resulted in the decrease of the inhibitory phosphorylation on Unc-51-like kinase-1 (ULK1) (a key protein in autophagy initiation), which may account for the enforced autophagy and cytokilling effect. Altogether, our results support the development of ALK and RAF1 combined inhibition as a new therapeutic approach in ALK+ ALCL.

CIP4 controls CCL19-driven cell steering and chemotaxis in chronic lymphocytic leukemia.

Solid tumor dissemination relies on the reprogramming of molecular pathways controlling chemotaxis. Whether the motility of nonsolid tumors such as leukemia depends on the deregulated expression of molecules decoding chemotactic signals remains an open question. We identify here the membrane remodeling F-BAR adapter protein Cdc42-interacting protein 4 (CIP4) as a key regulator of chemotaxis in chronic lymphocytic leukemia (CLL). CIP4 is expressed at abnormally high levels in CLL cells, where it is required for CCL19-induced chemotaxis. Upon CCL19 stimulation of CLL cells, CIP4 associates with GTP-bound Cdc42 and is recruited to the rear of the lamellipodium and along microspikes radiating through the lamellipodium. Consistent with its cellular distribution, CIP4 removal impairs both the assembly of the polarized lamellipodium and directional migration along a diffusible CCL19 gradient. Furthermore, CIP4 depletion results in decreased activation of WASP, but increased activation of PAK1 and p38 mitogen-activated protein kinase (MAPK). Notably, p38 MAPK inhibition results in impaired lamellipodium assembly and loss of directional migration. This suggests that CIP4 modulates both the WASP and p38 MAPK pathways to promote lamellipodium assembly and chemotaxis. Overall, our study reveals a critical role of CIP4 in mediating chemotaxis of CLL cells by controlling the dynamics of microspike-containing protrusions and cell steering.