Biology subjects

Muth, J.

Publications and source records attributed to Muth, J..

3 recordsLinked to original sources

bioRxiv2022

Unraveling the mystery behind the short-day-specific flowering of tobacco cultivar Maryland Mammoth

Flowering in day-neutral tobacco (Nicotiana tabacum) plants requires the photoperiod-dependent expression of members of the FLOWERING LOCUS T (FT)-like clade of phosphatidylethanolamine-binding proteins. FT-like floral activators and inhibitors compete for interaction with FD proteins to shift from vegetative to reproductive growth. In the short-day (SD) cultivar Maryland Mammoth (MM), vegetative growth persists under long-day (LD) conditions, generating unusually tall plants. We found that the major floral inducer under long-days (NtFT5) was expressed in MM and that NtFT5 overexpression induced flowering in MM plants under LD conditions. However, sequence analysis revealed a 2-bp deletion near the 3 end of NtFT5 in MM plants resulting in a frame shift which leads to an altered amino acid sequence and a premature stop codon. We found that the truncated NtFT5MM protein was still able to interact with tobacco FD proteins. However, constitutive overexpression under LD conditions in SD-specific flowering tobacco plants showed that NtFT5MM is a weaker floral inducer than NtFT5. Our data suggest that the truncation does not impair the stability of the NtFT5MM protein but may affect its binding affinity for NtFD1, probably resulting in the weaker expression of target genes. Our results therefore provide a potential explanation for the MM gigantism phenotype first observed more than 100 years ago. HighlightThe previously unexplained gigantism of Maryland Mammoth tobacco is caused by a truncated major floral activator protein that results in weaker activation and the inability to flower under long-day conditions.

plant biology↗

bioRxiv2020

TP53 abnormalities correlate with immune infiltration and are associated with response to flotetuzumab, an investigational immunotherapy, in acute myeloid leukemia

PurposeSomatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37-46% of acute myeloid leukemia (AML) cases with adverse risk cytogenetics and are associated with primary induction failure (PIF), high risk of relapse and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53 mutated AML and to determine whether TP53 abnormalities identify a patient subgroup that may benefit from T-cell targeting immunotherapy approaches. Experimental DesignThe NanoString Pan-Cancer IO 360 assay was used for the immune transcriptomic analysis of 64 diagnostic bone marrow (BM) samples from adults with TP53 mutated AML (n=42) or TP53 wild type AML (n=22), and 35 BM samples from heavily pretreated patients with relapsed/refractory (R/R) AML (11 cases with TP53 mutations and/or 17p deletion with genomic loss of TP53) who received immunotherapy with flotetuzumab, an investigational CD123xCD3 bispecific DART(R) molecule (NCT02152956). In silico data series included The Cancer Genome Atlas (TCGA) cohort and a Dutch-Belgian Cooperative Trial Group for Hematology-Oncology (HOVON) cohort. ResultsAll TCGA cases with TP53 mutations (n=13) expressed higher levels of negative immune checkpoints, inflammatory chemokines, interferon (IFN)-{gamma}-inducible molecules, and had a higher tumor inflammation signature (TIS) score, compared with TCGA cases with other risk-defining molecular lesions. The comparison between TP53 mutated and TP53 wild type primary BM samples showed higher expression of IFNG, FoxP3, immune checkpoints and markers of exhaustion and senescence in the former cohort and allowed the computation of a 34-gene immune classifier prognostic for overall survival. In vitro modeling experiments with AML cell lines showed heightened expression of IFN-{gamma} and inflammation pathway genes in KG-1 cells (loss-of-function mutation of TP53) compared with Kasumi-1 cells (gain-of-function mutation of TP53). Finally, 5 out of 11 (45.5%) patients with R/R AML and TP53 abnormalities showed evidence of anti-leukemic activity of flotetuzumab immunotherapy and had higher TIS, FoxP3, CD8 T-cell abundance, inflammatory chemokine and PD1 gene expression scores at baseline compared with non-responders. ConclusionsThis study provides evidence for a correlation between IFN-{gamma}-dominant immune subtypes and TP53 abnormalities. The anti-leukemic activity with flotetuzumab encourages further study of this immunotherapeutic approach in this patient subgroup.

immunology↗

bioRxiv2019

Immune Landscapes Predict Chemotherapy Resistance And Immunotherapy Response In Acute Myeloid Leukemia

This study dissected the complexity of the immune architecture of acute myeloid leukemia (AML) at high resolution and assessed its influence on therapeutic response. Using 387 primary bone marrow samples from three discovery cohorts of children and adults with AML, we defined immune-infiltrated and immune-depleted disease subtypes and unraveled critical differences in immune gene expression across age groups and disease stages. Importantly, interferon (IFN)-{gamma}-related mRNA profiles were predictive for both chemotherapy resistance and response of primary refractory/relapsed AML to flotetuzumab immunotherapy. Our compendium of microenvironmental gene and protein profiles sheds novel insights into the immuno-biology of AML and will inform the delivery of personalized immunotherapies to IFN-{gamma}-dominant AML subtypes.

immunology↗