Central diabetes insipidus (CDI) is a rare reported complication of acute myeloid leukemia (AML). The onset of AML-associated CDI often precedes the diagnosis of AML by weeks or months and is considered an adverse prognostic indicator in this setting. The mechanism of AML-associated CDI is not known; however, it is often reported in the setting of cytogenetic events resulting in MDS1 and EVI1 complex locus protein (MECOM) gene overexpression. Here, we describe a case of new onset CDI which preceded a diagnosis of AML by 1 month. We detail the clinical and laboratory evaluation of the patient’s CDI, and we describe the pathological and laboratory workup of their AML, which ultimately yielded a diagnosis of AML with myelodysplasia-related changes. Additional cytogenetic findings included the identification of the t (2;3)(p23;q27), which leads to MECOM gene overexpression and which to our knowledge has not previously been reported in the setting of AML-associated CDI. The patient received induction chemotherapy followed by allogeneic hematopoietic stem cell transplantation but experienced disease relapse and passed away nine months after initial diagnosis. We emphasize that new onset CDI can occur as a rare complication of AML where it portends a poor prognosis and may be related to AML subtypes displaying MECOM gene dysregulation.
17HIV-1 RNA genomes interact with diverse RNA binding proteins in the cytoplasm 18 including antiviral factor APOBEC3G (A3G) that, in the absence of viral Vif proteins, is 19 packaged into virions. When and where genome-A3G interactions are initiated in the host 20 cell is unknown. Here we use quantitative long-term (>24 h) live cell fluorescence video 21 microscopy and a new in-cell RNA-protein interaction assay (the "IC-IP") to describe 22 subcellular viral and A3G trafficking behaviors over the entire HIV-1 productive phase. 23Among other findings, we demonstrate that genome-A3G interactions are initiated in the 24 cytosol soon if not immediately after genome nuclear export; that A3G-genome 25 interactions are sufficiently strong so that tethering either factor to membranes inhibits 26 trafficking of the reciprocal binding partner; and that selective recognition of genomes 27 promotes consistent delivery of A3G to sites of virion assembly. Further elucidation of 28 RNA signature(s) detected by A3G may inform development of RNA-targeted antivirals. 29 RNA-and NC-dependent15-20. However, the relative contributions of genomes vs. host 50RNAs to this process remains controversial. On the one hand, A3G-RNA binding is 51 relatively promiscuous, with A3G incorporated into virus particles even when packageable 52 genomes are not expressed17,19. On the other hand, A3G incorporation levels are 53 moderately enhanced when genomes are present16,21; and A3G has been shown to 54 exhibit selective RNA-binding characteristics19,22 including a reported preference for G-55 rich segments of the HIV-1 genome20. 56Where and when A3G interfaces with Gag and/or genomes in the cell has also been 57 under investigation for some time with conflicting results. At steady-state, A3G is 58 distributed throughout the cytosol (the aqueous phase of the cytoplasm) and accumulates 59 to high levels at non-membranous cytoplasmic sites of mRNA decay known as processing 60 bodies (PBs)23,24. Cytosolic A3G is also rapidly re-localized to sites of translational 61 repression known as stress granules (SGs) in response to heat shock or oxidative 62 stress23,24. Initial studies proposed a functional link between PBs and A3G's antiviral 63 activity23,25,26. By contrast, more recent work has shown visible PBs to have little to no 64 discernible relevance to the HIV-1 life cycle27,28. 65The dynamic and complex nature of cytoplasmic RNA trafficking during HIV-1 virion 66 genesis may have obscured consistent prior observations made in fixed cells, 67 emphasizing a need for real-time characterization the host RBP response to HIV-1 68 infection at subcellular resolution. Accordingly, herein we set out to comprehensively 69 define the behaviors of HIV-1 RNA genomes, Gag, A3G, and additional PB and SG 70 markers over the entire viral productive phase using long-term (>24h) live cell video 71 microscopy. Our results expose single-cell A3G degradation and trafficking behaviors in 72 the presence or absence of Vif; and show that HIV-1 infection has little to no ne...
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