Acute myeloid leukaemia (AML) is a fatal disease for most patients. We have found that ferumoxytol (Feraheme®), a FDA approved iron oxide nanoparticle for iron deficiency treatment, demonstrates an anti-leukaemia effect in vitro and in vivo. Using leukaemia cell lines and primary AML patient samples, we show that low expression of the iron exporter ferroportin (FPN) results in a susceptibility of these cells by an increase in intracellular iron from ferumoxytol. The reactive oxygen species produced by free ferrous iron leads to increased oxidative stress and cell death. Ferumoxytol treatment results in a significant reduction of disease burden in a murine leukaemia model and patient-derived xenotransplants (PDX) bearing leukaemia cells with low FPN expression. Our findings show how a clinical nanoparticle considered previously largely biologically inert could be rapidly incorporated into clinical trials for patients with leukaemia with low FPN levels.

The unfolded protein response (UPR) is a cellular mechanism that is triggered in order to cope with the stress caused by the accumulation of misfolded proteins in the endoplasmic reticulum (ER). This response is initiated by the endoribonuclease inositol-requiring enzyme 1 (IRE1), activating transcription factor 6 (ATF6), and PKR-like ER kinase, which increase the expression of the genes involved in the folding and degradation processes and decrease the protein input into the ER by inhibiting translation. It has been shown that viruses both induce and manipulate the UPR in order to protect the host cells from an ER stress-mediated death, thus permitting the translation of viral proteins and the efficient replication of the virus. To understand the cellular events that occur during the rotavirus replication cycle, we examined the activation of the three UPR arms following infection, using luciferase reporters driven by promoters of the ER stress-responsive genes and real-time reverse transcription-PCR to determine the levels of the stress-induced mRNAs. Our findings indicated that during rotavirus infection two of the three arms of the UPR (IRE1 and ATF6) become activated; however, these pathways are interrupted at the translational level by the general inhibition of protein synthesis caused by NSP3. This response seems to be triggered by more than one viral protein synthesized during the replication of the virus, but not by the viral double-stranded RNA (dsRNA), since cells transfected with psoralen-inactivated virions, or with naked viral dsRNA, did not induce UPR.

As intracellular parasites, viruses require a host cell in order to replicate. However, they face a series of cellular responses against infection. One of these responses is the activation of the double-stranded RNA (dsRNA)-activated protein kinase R (PKR). PKR phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), which in turn results in global protein synthesis inhibition and formation of stress granules (SGs). Recent studies have shown that SGs can interfere with the replicative cycle of certain viruses. This review addresses how viruses have evolved different control strategies at the SG level to ensure an efficient replication cycle during the cellular stress response triggered by the viral infection.

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Acute myeloid leukemia (AML) is a disease with high incidence of relapse that is originated and maintained from leukemia stem cells (LSCs). Hematopoietic stem cells can be distinguished from LSCs by an array of cell surface antigens such as CD123, thus a candidate to eliminate LSCs using a variety of approaches, including CAR T cells. Here, we evaluate the potential of allogeneic gene-edited CAR T cells targeting CD123 to eliminate LSCs (UCART123). UCART123 cells are TCRαβneg T cells generated from healthy donors using TALEN® gene-editing technology, decreasing the likelihood of graft vs host disease. As safety feature, cells express RQR8 to allow elimination with Rituximab. UCART123 effectively eliminates AML cells in vitro and in vivo with significant benefits in overall survival of AML-patient derived xenograft mice. Furthermore, UCART123 preferentially target AML over normal cells with modest toxicity to normal hematopoietic stem/progenitor cells. Together these results suggest that UCART123 represents an off-the shelf therapeutic approach for AML.