A Recurrent STAT5BN642H Driver Mutation in Feline Alimentary T Cell Lymphoma

Abstract

Alimentary lymphomas arising from T cells are rare and aggressive malignancies in humans. In comparison, they represent the most common anatomical form of lymphoma in cats. Due to the low prevalence in humans, the underlying pathomechanism for these diseases is poorly characterised, limiting experimental analysis and therapeutic exploration. To date, activating mutations of the JAK/STAT core cancer pathway and particularly the STAT5B oncoprotein have been identified in human enteropathy-associated T cell lymphoma. Here, we describe a high homology of human and feline STAT3 and STAT5B proteins and strong conservation at the genomic level. Analysis of 42 samples of feline T cell alimentary lymphoma reveals broad activation of STAT3 and STAT5B. Screening for known activating mutations in STAT3 or STAT5B identifies the presence of the STAT5BN642H driver mutation in feline enteropathy-associated T cell lymphoma in 7 out of 42 (16.67%) samples in total. Regarding lymphoma subtypes, the majority of mutations with 5 out of 17 (29.41%) cases were found in feline enteropathy-associated lymphoma type II (EATL II). This identification of an oncogenic STAT5B driver mutation in felines recapitulates the genetic situation in the corresponding human disease, thereby establishing the cat as a potential new model for a rare and incurable human T cell disease.

ACVIMconsensus statement guidelines on diagnosing and distinguishing low‐grade neoplastic from inflammatory lymphocytic chronic enteropathies in cats

“…Minimal and mostly gradual differences within the fecal microbiome and metabolome of cats with LGITL or LPE have been reported and there is high similarity with perturbations seen in humans with IBD 32,43 . Recently dysregulations of the janus kinase (JAK)‐signal transducer and activator of transcription (STAT) pathway with high expression of STAT5 were documented in cats with LGITL 3,19 . The JAK − STAT pathway plays a critical regulatory role in lymphocyte development, differentiation, and proliferation, and its dysregulation has been shown to be a major oncogenic driver in several lymphoma subtypes in humans 44 …”

“…Although EATL‐Type I is associated with celiac disease, EATL‐Type II (MEITL) is less common and infrequently associated with celiac disease. Because of its morphologic features, including size of lymphocytes and epitheliotropism, previous studies suggested LGITL as a relevant model of MEITL 19,34,154 . However, despite LGITL having histologic similarities with MEITL, the clinical course of these 2 diseases and their immunophenotyping differ markedly.…”

“…Part of the veterinary community has argued that a comprehensive diagnostic evaluation of cats with CE may be unnecessary because it does not appear to change prognosis or treatment. However, data from more recent studies indicate that prognosis and treatment strategy may need adjustment based on the underlying diagnosis 18,19 . An evaluation including intestinal biopsies does not only exclude other differential diagnoses including large cell lymphomas, infectious, eosinophilic, or mast cell disease but also could allow for a more accurate prognosis and treatment plan in the future.…”

Feline Oncogenomics: What Do We Know about the Genetics of Cancer in Domestic Cats?

“…Investigations into Fas, which belongs to the tumour necrosis factor receptor family and transduces the death signal after binding to the Fas ligand, led to one group detecting FAS mRNA in 7/11 feline lymphoma samples, with some samples showing the presence of alternatively spliced transcripts (similar to what they had found using feline lymphoma cell lines) [ 35 ]. More recently, analysis of 42 feline T-cell GI lymphoma samples by immunohistochemistry demonstrated broad activation of STAT3 and STAT5B, and screening for known activating mutations in the same samples identified the presence of the STAT5B N642H driver mutation (found in humans with type II enteropathy-associated T-cell lymphoma [ 36 ]) in 7/42 (17%) samples, with the majority being found in the low grade subtype (known as enteropathy-associated T-cell lymphoma type II or small cell lymphoma), which is the most common subtype [ 37 ].…”

Comment on Kieslinger et al. A Recurrent STAT5BN642H Driver Mutation in Feline Alimentary T Cell Lymphoma. Cancers 2021, 13, 5238

“…We have read with great interest the recently published article by M. Kieslinger et al in Cancers Journal [ 1 ]. In this retrospective study, the authors report the JAK-STAT pathway deregulation in gastrointestinal T-cell lymphoma in cats, and particularly STAT5B broad activation.…”