Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model

Duran‐Struuck, Raimon; Matar, Abraham J.; Huang, Christene A.

doi:10.3389/fgene.2015.00332

Cited by 10 publications

(9 citation statements)

References 38 publications

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“…The information in this report addresses a gap in cytogenic investigations of hematologic malignancies within miniature swine in the veterinary scientific literature that lack the comprehensive clinical progression seen in this report for detection and diagnosis of naturally occurring porcine CML (16). Hematologic malignancies in miniature swine are frequently reported as incidental findings; most in depth reports are from line-bred or genetically engineered animals ( Supplementary Table 2) (4,5,19).…”

Section: Discussionmentioning

confidence: 99%

“…A BCR-ABL translocation between chromosomes 9 and 26, the "Raleigh" chromosome, was identified in several cases of canine CML (12)(13)(14). A potential association between chronic myelogenous (basophilic) leukemia and a Philadelphia gene sequence in Yucatan pigs is lacking in currently available literature (5,9,11,12,15,16). Material in this novel report provides vital information that will contribute to accurate, pre-mortem diagnosis of Ph+ CML in outbred Yucatan swine.…”

Section: Introductionmentioning

confidence: 96%

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Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

et al. 2020

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Background: Chronic myelogenous leukemia (CML) is a clonal proliferative disorder of the myeloid, megakaryocyte, and erythroid lineages. The onset and subsequent progression of CML is well-described in humans. There is comparably little information surrounding CML progression in veterinary species, including Yucatan miniature swine that are common for preclinical pharmaceutical and device testing. In humans, more than 90% of CML cases are associated with a chromosomal translocation that results in the Philadelphia gene (BCR/ABL mutation). In this report, the presence of the Philadelphia gene in a Yucatan burrow was confirmed in white blood cells collected prior to onset of clinical signs with primers designed from the human BCR/ABL sequence. Case Presentation: A 24 month old, 70 kg, Yucatan barrow received a prefabricated bovine cortical bone xenograft following a unilateral zygomatic ostectomy for a preclinical study. Complete blood count and serum chemistries were performed prior to and 28, 53, 106, and 129 days after facial surgery. Fifty three days after surgery, a bone marrow biopsy was performed due to anorexia, severe basophilia, and mild anemia. A finding of a moderate increase in basophilic precursors in bone marrow cytology was followed by lymphocyte immunophenotyping via flow cytometry and RT-PCR amplification of the Philadelphia gene in white blood cell samples from the affected barrow and an unaffected barrow in the same treatment group. Bone marrow, lymph node, liver, spleen, lung, kidney, and adrenal gland lesions of mostly myeloblasts were identified after the affected barrow died 146 days after surgery. Flow cytometry confirmed lymphopenia and suggested basophilia, and RT-PCR established the presence of the BCR/ABL gene. Conclusions: The information in this report confirms the presence of the BCR/ABL mutation and documents progression of chronic myelogenous (basophilic) leukemia from a chronic phase to a terminal blast crisis in an adult Yucatan barrow. The natural occurrence and progression of CML associated with the BCR/ABL mutation in miniature Takawira et al. Porcine Chronic Myelogenous Leukemia swine establishes potential for future porcine models of human CML. The information also establishes a genetic test to confirm porcine CML to prevent inadvertent attribution of clinical signs to treatment complications during preclinical testing.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

et al. 2020

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“…There are additional facets to the robustness and evolvability of transcriptional and RNA-mediated gene regulation that we do not study here. For example, the robustness of transcriptional regulation can be enhanced by homotypic clusters of TF binding sites, shadow enhancers, and redundant TFs ( 62 ), whereas the evolvability of RNA-mediated gene regulation can be enhanced by alternative splicing, alternative polyadenylation, and RNA editing ( 63 ). Even in the context of nucleic acid binding sites, which are the focus of this study, there is an additional facet to evolvability that we do not consider but that may further contribute to the greater evolvability of TF binding sites.…”

Section: Discussionmentioning

confidence: 99%

RNA-mediated gene regulation is less evolvable than transcriptional regulation

Payne

Khalid

Wagner

2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceCells regulate the activity of genes in a variety of ways. For example, they regulate transcription through DNA binding proteins called transcription factors, and they regulate mRNA stability and processing through RNA binding proteins. Based on current knowledge, transcriptional regulation is more widespread and is involved in many more evolutionary adaptations than posttranscriptional regulation. The reason could be that transcriptional regulation is studied more intensely. We suggest instead that transcriptional regulation harbors an intrinsic evolutionary advantage: when mutations change transcriptional regulation, they are more likely to bring forth novel patterns of such regulation. That is, transcriptional regulation is more evolvable. Our analysis suggests a reason why a specific kind of gene regulation is especially abundant in the living world.

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“…Hematological malignancies in swine—reviewed in Ref. ( 146 )—were first reported as early as 1865 ( 147 ) but as of yet, there is no porcine model of hematological malignancies that can be reliably induced and consistently reproduced. There is a wide spectrum of potential immunotherapy targets, cellular therapies, and gene targets that can be used to eradicate or control malignant hematopoietic stem cells.…”

Section: Future Modeling Capabilitiesmentioning

confidence: 99%

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform

et al. 2017

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Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model—the Oncopig Cancer Model (OCM)—as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D, the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.

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Myeloid Leukemias and Virally Induced Lymphomas in Miniature Inbred Swine: Development of a Large Animal Tumor Model

Cited by 10 publications

References 38 publications

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

Association of Chronic Myelogenous (Basophilic) Leukemia and the BCR/ABL Mutation in a Yucatan Barrow (Sus scrofa domestica)

RNA-mediated gene regulation is less evolvable than transcriptional regulation

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform

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