Dataset Information

Parallel evolution of two distinct lymphoid proliferations in clonal haematopoiesis.

ABSTRACT:

Aims

Angioimmunoblastic T-cell lymphoma (AITL) is genetically characterized by TET2 and DNMT3A mutations occurring in haematopoietic progenitor cells, and late events (e.g. the RHOA-G17V mutation) associated with malignant transformation. As TET2/DNMT3A-mutated progenitor cells can differentiate into multilineage progenies and give rise to both AITL and myeloid neoplasms, they may also have the potential to lead to other metachronous/synchronous neoplasms. We report two cases showing parallel evolution of two distinct potentially neoplastic lymphoid proliferations from a common mutated haematopoietic progenitor cell population.

Methods and results

Both cases presented with generalized lymphadenopathy. In case 1 (a 67-year-old female), an initial lymph node (LN) biopsy was dismissed as reactive, but a repeat biopsy showed a nodal marginal zone lymphoma (NMZL)-like proliferation with an increase in the number of T-follicular helper (TFH) cells. Immunohistochemistry, and clonality and mutational analyses by targeted sequencing of both whole tissue sections and microdissected NMZL-like lesions, demonstrated a clonal B-cell proliferation that harboured the BRAF-G469R mutation and shared TET2 and DNMT3A mutations with an underlying RHOA-G17V-mutant TFH proliferation. Review of the original LN biopsy showed histological and immunophenotypic features of AITL. In case 2 (a 66-year-old male), cytotoxic T-cell lymphoma with an increase in the number of Epstein-Barr virus-positive large B cells was diagnosed on initial biopsy. On review together with the relapsed biopsy, we identified an additional occult neoplastic TFH proliferation/smouldering AITL. Both T-cell proliferations shared TET2 and DNMT3A mutations while RHOA-G17V was confined to the smouldering AITL.

Conclusions

In addition to demonstrating diagnostic challenges, these cases expand the potential of clonal haematopoiesis in the development of different lineage neoplastic proliferations.

SUBMITTER: Attygalle AD

PROVIDER: S-EPMC9310594 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Picobirnaviruses (PBVs) are small, bi-segmented, double-stranded RNA viruses frequently associated with gastrointestinal and recently linked to respiratory infections. Detected in hosts from distant biological kingdoms, debate swirls as to their age and origins and whether they are prokaryotic or eukaryotic viruses. Our evolutionary analysis revealed a contemporaneous emergence for PBV, as PBV-R1&3 species arose ~350 years ago with both segments, whereas the more ancient species, PBV-R2, initially lacked capsid. Integrated phylogenetic reconstruction defined two origins for PBV, determining PBV-R1&3 species descended from Reovirus and PBV-R2 branched with Partitivirus ancestors. These results, coupled with the heterogeneity of Shine-Dalgarno motifs, argue against a prokaryotic origin. Epistatic interactions identified in the RdRp of PBV-R1&3 evidenced the constraints imposed by vertebrate host immunity, whereas its absence in PBV-R2 concurs with its fungal origin. After acquisition of capsid, PBV-R2 increased its adaptive and functional divergences in RdRp domains and the compactness of its RNA structure to enable encapsidation. While their pathogenicity remains an open question, picobirnaviruses likely originated from both fungal and avian hosts: parallel evolution mechanisms have driven the genetic similarities shared among present-day PBV species.IMPORTANCEPicobirnaviruses (PBVs) are highly heterogeneous viruses encoding a capsid and RdRp. Detected in a wide variety of animals with and without disease, their association with gastrointestinal and respiratory infections, and consequently their public health importance, has rightly been questioned. Determining the "true" host of Picobirnavirus lies at the center of this debate, as evidence exists for them having both vertebrate and prokaryotic origins. Using integrated and time-stamped phylogenetic approaches, we show they are contemporaneous viruses descending from two different ancestors: avian Reovirus and fungal Partitivirus. The fungal PBV-R2 species emerged with a single segment (RdRp) until it acquired a capsid from vertebrate PBV-R1 and PBV-R3 species. Protein and RNA folding analyses revealed how the former came to resemble the latter over time. Thus, parallel evolution from disparate hosts has driven the adaptation and genetic diversification of the Picobirnaviridae family.