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Mishra, T.

Publications and source records attributed to Mishra, T..

2 recordsLinked to original sources
bioRxiv2020

Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess crosslineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without PDC expansion. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.Competing Interest StatementConflict-of-interest disclosure: W.X. has received research support from Stemline Therapeutics. S.F.C. is a consultant for Imago Biosciences and has received honoraria from DAVA Oncology. A.D.G. served on advisory boards or as a consultant for Abbvie, Aptose, Celgene, Daiichi Sanyko, Genentech, received research funding from Abbvie, ADC Therapeutics, Aprea, AROG, Daiichi Sanyko, Pfizer, received Honoraria from Dava Oncology. R.K.R has received consulting fees from: Constellation, Incyte, Celgene, Promedior, CTI, Jazz Pharmaceuticals, Blueprint, Stemline, and research funding from Incyte, Constellation, and Stemline Therapeutics. M.S.T has received research funding from AbbVie, Cellerant, Orsenix, ADC Therapeutics, Biosight, Glycomimetics, Rafael Pharmaceuticals and Amgen. He also served on advisory Boards for AbbVie, BioLineRx, Daiichi-Sankyo, Orsenix, KAHR, Rigel, Nohla, Delta Fly Pharma, Tetraphase, Oncolyze, Jazz Pharma, Roche, Biosight and Novartis. He received royalties from UpToDate. R.L.L. is on the supervisory board of Qiagen and is a scientific advisor to Loxo (until 2019), Auron, Ajax, Mission Bio, Imago, C4 Therapeutics and Isoplexis, which each include an equity interest. He receives research support from and consulted for Celgene and Roche, he has received research support from Prelude Therapeutics, and he has consulted for Incyte, Novartis and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews.View Full Text

pathology↗
bioRxiv2019

Highly clade-specific biosynthesis of rhamnose: present in all plants and in only 42% of prokaryotes.Only Pseudomonas uses both D- and L-rhamnose

Rhamnose is a constituent of lipo- and capsular polysaccharides, and cell surface glycoproteins. L-rhamnose is biosynthesized by the rml or udp pathway and D-rhamnose by the gdp pathway. Disruption of its biosynthesis affects survival, colonisation, etc. Rhamnosides are commercially important in pharmaceutical and cosmetics industries. HMM profiles were used to investigate the prevalence of the three pathways in completely sequenced genomes and metagenomes. The three pathways are mutually exclusive except in Pseudomonas which has both rml and gdp pathways. The rml pathway is restricted to bacteria (42% genomes), archaea (21%) and bacteriophages, and absent in eukaryotes and other viruses. The gdp pathway is restricted to Pseudomonas and Aneurinibacillus. The udp pathway is primarily found in plants, fungi and algae, and in human faecal metagenomic samples. The rml pathway is found in >40% genomes of Actinobacteria, Bacteroidetes, Crenarchaeota, Cyanobacteria, Fusobacteria and Proteobacteria but in <20% genomes of Chlamydiae, Euryarchaeota and Tenericutes. The udp pathway is found in all genomes of Streptophyta, <=25% genomes of Ascomycota and Chordata, and none of the genomes of Arthropoda and Basidiomycota. Some genera which lack any of these pathways are Chlamydia, Helicobacter, Listeria, Mycoplasma, Pasteurella, Rickettsia and Staphylococcus. Organisms such as E. coli and Salmonella enterica showed significant strain-specific differences in the presence/absence of rhamnose pathways. Identification of rhamnose biosynthesis genes facilitates profiling their expression pattern, and in turn, better understanding the physiological role of rhamnose. Knowledge of phylogenetic distribution of biosynthesis pathways helps in fine graining the taxonomic profiling of metagenomes. AUTHOR SUMMARYIn the present study, we have investigated the prevalence of rhamnose biosynthesis pathways in completely sequenced genomes and metagenomes. It is observed that the prevalence of rhamnose is highly clade specific: present in all plants but in less than half of all prokaryotes. Among chordates, only the Chinese rufous horseshoe bat has rhamnose biosynthesis pathway and this exclusive presence is quite baffling. The effect of disrupting rhamnose biosynthesis has been reported in a few prokaryotes and all these cases pointed to the essentiality of rhamnose for critical physiological processes such as survival, colonisation, etc. In this background, it is surprising that many of the prokaryotes such as Escherichia coli and Salmonella enterica show significant strain-specific differences in the presence/absence of rhamnose pathway. This study will facilitate the experimental characterization of rhamnose biosynthesis genes in organisms where this pathway has not been characterised yet, eventually leading to the elucidation of the biological role of rhamnose. Phylum-, genus-, species- and strain-level differences found with respect to presence of rhamnose biosynthesis pathway genes can be used as a tool for taxonomic profiling of metagenome samples. This study could also annotate a significant number of orphan proteins in the TrEMBL database.

genomics↗