Development of Novel Patient-derived Xenograft Model of Chronic Lymphocytic Leukemia

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F65269705%3A_____%2F20%3A00073419" target="_blank" >RIV/65269705:_____/20:00073419 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.ceitec.eu/abstract-book-final-docx-pdf/f36324" target="_blank" >https://www.ceitec.eu/abstract-book-final-docx-pdf/f36324</a>

DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Development of Novel Patient-derived Xenograft Model of Chronic Lymphocytic Leukemia

Popis výsledku v původním jazyce

Patient-derived xenografts (PDX) enable therapy testing and study of cancer evolution on a genetic background of individual patients. We aim to develop a novel murine PDX model of chronic lymphocytic leukemia (CLL), an incurable B-cell malignancy with characteristic dependence on human immune microenvironment. In currently available PDXs proliferation of CLL lymphocytes is maintained by presence of autologous T-cells, however, in few weeks these spontaneously overgrow and eliminate engrafted CLL cells. Our intention is to replace T-cells and supply pro-proliferative and pro-survival signals by their introduction into supportive cell line co-implanted with purified CLL cells. We genetically engineered an adherent supportive cell line, which in coculture induces long term survival and major proliferation of primary CLL cells in vitro. We seeded the cell line on collagen scaffolds, implanted subcutaneously into immunodeficient mice (NSG) and injected highly purified CLL cells (65-350x106 cells per animal). By this we have achieved growth of B-cells in 2 out of 5 transplanted CLL samples; in both cases positive for Epstein- Barr virus (EBNA1 gene). CLL clonal relationship to the patient&apos;s sample was confirmed in one of the grafts by IGHV rearrangement analysis. In this case cells formed a solid tumor positive for CD20/CD45/CD79a cell-surface markers (detected by immunohistochemistry), and cells were found both in peripheral blood and murine spleen, which is a typical site of CLL infiltration in humans. We plan to further assess different ways of transplantation and modify the supportive cells. The established model will be used for testing of novel therapeutic combinations and studies of CLL biology.

Název v anglickém jazyce

Development of Novel Patient-derived Xenograft Model of Chronic Lymphocytic Leukemia

Popis výsledku anglicky

Patient-derived xenografts (PDX) enable therapy testing and study of cancer evolution on a genetic background of individual patients. We aim to develop a novel murine PDX model of chronic lymphocytic leukemia (CLL), an incurable B-cell malignancy with characteristic dependence on human immune microenvironment. In currently available PDXs proliferation of CLL lymphocytes is maintained by presence of autologous T-cells, however, in few weeks these spontaneously overgrow and eliminate engrafted CLL cells. Our intention is to replace T-cells and supply pro-proliferative and pro-survival signals by their introduction into supportive cell line co-implanted with purified CLL cells. We genetically engineered an adherent supportive cell line, which in coculture induces long term survival and major proliferation of primary CLL cells in vitro. We seeded the cell line on collagen scaffolds, implanted subcutaneously into immunodeficient mice (NSG) and injected highly purified CLL cells (65-350x106 cells per animal). By this we have achieved growth of B-cells in 2 out of 5 transplanted CLL samples; in both cases positive for Epstein- Barr virus (EBNA1 gene). CLL clonal relationship to the patient&apos;s sample was confirmed in one of the grafts by IGHV rearrangement analysis. In this case cells formed a solid tumor positive for CD20/CD45/CD79a cell-surface markers (detected by immunohistochemistry), and cells were found both in peripheral blood and murine spleen, which is a typical site of CLL infiltration in humans. We plan to further assess different ways of transplantation and modify the supportive cells. The established model will be used for testing of novel therapeutic combinations and studies of CLL biology.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů