Roboz, G. J. | bioRxiv Science

bioRxiv2026

eIF4E and Ezrin cooperate in pseudopods to drive a localized migratory translation program in acute myeloid leukemia

Aggressive subtypes of acute myeloid leukemia (AML) are characterized by increased migratory behavior and poor prognosis prioritizing the need for uncovering relevant mechanisms. While attributed to transcriptional changes, these AMLs manifest dysregulated eIF4E implicating disrupted mRNA metabolism. Here, we observed in AML mouse models, patient specimens, and cell lines that eIF4E drives motility, colonization, engraftment and AML progression. AML cells migrate utilizing Ezrin-positive pseudopods. Unexpectedly, we discovered that eIF4E interacts with Ezrin, that these physically associated factors are required and cooperated to drive an on-demand translation program in pseudopods for motility. Indeed, pseudopods were sites of eIF4E- and Ezrin-dependent translation by implementing the first method to directly mark active ribosomes in situ (Visualizing Translation Activity using RiboLace, VISTA-R). Biochemically, Ezrin bound eIF4E, ribosomal components, and mRNAs consistent with our observed Ezrin-dependent modulation of protein production. This unprecedented physical coupling of motility and translation provisions migratory sites to sustain AML progression. Highlights- eIF4E reduction impairs AML cell motility and disease progression - eIF4E-dependent motility requires Ezrin - Ezrin binds eIF4E, transcripts encoding motility factors and active ribosomes - VISTA-R enabled visualization of active ribosomes and translationally active pseudopods (T-PODs) - T-PODs provide novel on-demand localized translation to sustain mobility at migratory sites Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/707190v2_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@164f191org.highwire.dtl.DTLVardef@2f8928org.highwire.dtl.DTLVardef@d5ad7forg.highwire.dtl.DTLVardef@719a69_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2017

Somatic Mutations Predict Acute Myeloid Leukemia Years Before Diagnosis

BackgroundSomatic mutations observed in clonal hematopoiesis are associated with increased age and risk of hematological malignancies. However, the limited number of acute myeloid leukemia (AML) patients in studies of clonal hematopoiesis thus far has precluded determination of the spectrum of mutations leading to AML and their impact on risk and time to diagnosis.\n\nMethodsThe relationship between baseline mutations and subsequent AML was determined in a case-control study design. 212 women eventually diagnosed with AML (median time: 9.8 years) were identified from the Womens Health Initiative cohort alongside 212 matched AML-free controls. Deep sequencing of 67 genes was performed on DNA isolated from peripheral blood to detect subclonal mutations.\n\nResultsThe presence of any mutation was associated with increased odds of eventual AML (odds ratio [OR] 4.0; 95% confidence interval [CI], 2.5-6.3). These odds were further elevated with mutations in IDH1/2 (OR 8.4; 95% CI, 1.4-51.9), TP53 (OR 54.2; 95% CI, 2.9-1017.7), or spliceosome genes (OR 5.6; 95% CI, 1.5-20.6). Eventual AML diagnosis occurred in all or most participants with mutations in TP53 (N=23/23) or IDH1/2 (N=15/16). Mutations indicated sooner AML diagnosis (median 8.0 vs. 11.9 years; P < 0.001) with TP53 mutations demonstrating increased odds of AML within 5 years (OR 3.6; 95% CI, 1.4-9.1).\n\nConclusionsMutations are present in peripheral blood of AML patients a decade prior to AML diagnosis with mutations in TP53 producing especially rapid presentation. Strategies for monitoring of high-risk populations are needed and clinical trials of potential early interventions can be considered.

cancer biology↗