BackgroundVimentin (VIM) is a type III intermediate filament that maintains cell integrity, and is involved in cell migration, motility and adhesion. When overexpressed in solid cancers, vimentin drives epithelial to mesenchymal transition (EMT) and ultimately, metastasis. The effects of its overexpression in AML are unclear.MethodsIn this study, we analyzed the TCGA data of 173 AML patients for which complete clinical and expression data were available. In this analysis, we assessed the association between VIM mRNA expression and patient’s clinical and molecular characteristics including clinical outcome.ResultsVIM overexpression was associated with higher white blood count (< p = 0.0001). Patients with high VIM expression have worse overall survival (OS) and disease-free survival (DFS) compared with patients with low VIM expression (median OS; 7.95 months vs 19.2 months; p = 0.029). After age-stratification, high VIM expression was significantly associated with worse overall survival in older patients (age ≥ 60; median OS: 5.4 vs 9.9 months: p = 0.0257) but not in younger patients (age < 60). In stratification analysis according to cytogenetic status, high VIM expression was significantly associated with shorter OS (7.95 vs 24.6 months: p = 0.0102) in cytogenetically normal, but not in cytogenetic abnormal AML.ConclusionsCollectively, the data indicate that overexpression of the EMT marker vimentin is associated with poor clinical outcome in older patients with cytogenetically normal AML; and therefore may play a role in this disease.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1539-y) contains supplementary material, which is available to authorized users.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected several millions and killed more than quarter of a million worldwide to date. Important questions have remained unanswered: why some patients develop severe disease, while others do not; and what roles do genetic variabilities play in the individual immune response to this viral infection. Here, we discuss the critical role T cells play in the orchestration of the antiviral response underlying the pathogenesis of the disease, COVID-19. We highlight the scientific rationale for comprehensive and longitudinal TCR analyses in COVID-19 and reason that analyzing TCR repertoire in COVID-19 patients would reveal important findings that may explain the outcome disparity observed in these patients. Finally, we provide a framework describing the different strategies, the advantages, and the challenges involved in obtaining useful TCR repertoire data to advance our fight against COVID-19. The COVID-19 Immune Conundrum HighlightsThe COVID-19 pandemic revealed vulnerability in elderly population and underscored the role of the aging immune system in the fight against emerging infections.

Acute myeloid leukemia (AML) is a devastating hematologic malignancy that affects the hematopoietic stem cells. The 5-year overall survival (OS) of patients with AML is less than 30%, highlighting the urgent need to identify new therapeutic targets. Here, we analyze gene expression datasets for genes that are differentially overexpressed in AML cells compared with healthy hematopoietic cells. We report that apolipoprotein C2 (APOC2) mRNA is signifi cantly overexpressed in AML, particularly in patients with mixed-lineage leukemia rearrangements. By multivariate analysis, high APOC2 expression in leukemia blasts is signifi cantly associated with decreased OS (HR: 2.51; 95% CI, 1.03-6.07; P = 0.04). APOC2 is a small secreted apolipoprotein that constitutes chylomicrons, very-low-density lipoproteins, and high-density lipoproteins with other apolipoproteins. APOC2 activates lipoprotein lipase and contributes to lipid metabolism. By gain and loss of function approaches in cultured AML cells, we demonstrate that APOC2 promotes leukemia growth via CD36-mediated LYN-ERK signaling activation. Knockdown or pharmacological inhibition of either APOC2 or CD36 reduces cell proliferation, induces apoptosis in vitro , and delays leukemia progression in mice. Altogether, this study establishes APOC2-CD36 axis as a potential therapeutic target in AML. SIGnIFICAnCE: The majority of patients with AML die within fi ve years of diagnosis. We reveal that lipid transporter APOC2 is elevated in AML and promotes leukemic cell metabolism and growth via CD36, and provide preclinical evidence that targeting this pathway may be benefi cial in AML.

Current model for spindle positioning requires attachment of the microtubule (MT) motor cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect spindle displacement. How dynein is anchored by cortical attachment machinery to generate large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the yeast dynein attachment molecule, is limited by its assembly factor Mdm36. Overexpression of Mdm36 results in an overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that mediate dynein-anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 clusters containing only ∼6 copies of Num1 molecules mediate dynein-dependent spindle pulling via lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with mitochondrial tethering but not dynein-based spindle-pulling function of Num1. We propose that formation of small ensembles of attachment molecules is sufficient for dynein anchorage and cortical generation of large spindle-pulling force.

13 Current model for spindle positioning requires attachment of the microtubule (MT) motor 14 cytoplasmic dynein to the cell cortex, where it generates pulling force on astral MTs to effect 15 spindle displacement. How dynein is anchored by cortical attachment machinery to generate 16 large spindle-pulling forces remains unclear. Here, we show that cortical clustering of Num1, the 17 yeast dynein attachment molecule, is limited by Mdm36. Overexpression of Mdm36 results in an 18 overall enhancement of Num1 clustering but reveals a population of dim Num1 clusters that 19 mediate dynein-anchoring at the cell cortex. Direct imaging shows that bud-localized, dim Num1 20 clusters containing only ~6 copies of Num1 molecules mediate dynein-dependent spindle 21 pulling via lateral MT sliding mechanism. Mutations affecting Num1 clustering interfere with 22 mitochondrial tethering but not dynein-based spindle-pulling function of Num1. We propose that 23 formation of small ensembles of attachment molecules is sufficient for dynein anchorage and 24 cortical generation of large spindle-pulling force. 25 26 4 al. , 2010; Lackner et al., 2013). Although it is well-accepted that dynein exerts spindle pulling 53 force at cortical Num1 sites, the abundance and heterogeneity of Num1 patches along the cell 54 cortex (Heil-Chapdelaine et al., 2000; Omer et al., 2018; Schmit et al., 2018) has made it 55 impossible to follow the effects of astral MT plus end interaction with individual cortical Num1 56 sites, a prerequisite for understanding how clustering might impact dynein force amplification. 57 To our knowledge, contacts between astral MT plus end and individual Num1 foci have not 58 been observed for MT sliding, the in vivo hallmark of dynein-mediated spindle pulling (Adames 59 and Cooper, 2000; Yeh et al., 2000), hence the size of Num1 clusters required for this classic 60 dynein-dependent microtubule-cortex interaction remains unknown. Additionally, recent work61 shows that organelles such as mitochondria and endoplasmic reticulum (ER) are involved in 62 regulating Num1 cluster formation: a subset of cortical Num1 clusters appears to require 63 mitochondria for their assembly (Kraft and Lackner, 2017), whereas another population requires 64 the ER tethering proteins Scs2/Scs22 for their distribution throughout the cell cortex (Chao et 65 al., 2014; Omer et al., 2018). The general hypothesis emerging from these studies is that 66 distinct populations of Num1 clusters might exist at the cell periphery, but whether different 67 pools of Num1 could be performing different Num1 functions -namely, dynein anchoring and 68 mitochondrial tethering -remains a total mystery.69 Here, we set out to characterize the role of Mdm36 in Num1 clustering and found that, in 70 contrast to the prevailing notion for dynein-anchoring proteins, enhancing Num1 clustering 71 unexpectedly reduces dynein recruitment to the cell cortex, but without affecting dynein function 72 in spindle positioning. We report direct observation of MT sliding occurring upon...