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Characterization of the functional role of prdm1 in normal and neoplastic NK-cells

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  1. Tez No: 401331
  2. Yazar: CAN KÜÇÜK
  3. Danışmanlar: PROF. WING C. JOHN CHAN
  4. Tez Türü: Doktora
  5. Konular: Onkoloji, Oncology
  6. Anahtar Kelimeler: Belirtilmemiş.
  7. Yıl: 2012
  8. Dil: İngilizce
  9. Üniversite: University of Nebraska at Omaha
  10. Enstitü: Yurtdışı Enstitü
  11. Ana Bilim Dalı: Belirtilmemiş.
  12. Bilim Dalı: Belirtilmemiş.
  13. Sayfa Sayısı: 176

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Özet (Çeviri)

Natural Killer Cell lymphoma/leukemias (NKCLs) are rare but aggressive neoplasms with very poor prognosis. Through the use of cytogenetic and high-resolution array-comparative genomic hybridization (a-CGH) techniques, mono-allelic deletion of 6q21 was identified as the most frequent genomic abnormality in NKCLs. In the experiments performed for this dissertation, we identified and further narrowed down the mono-allelic deletion of 6q21 using high-resolution BAC a-CGH. By correlating the gene expression profiles (GEP) with the deletion status of NKCL samples and performing a literature search, we identified ATG5, AIM1 and PRDM1 as candidate tumor suppressor genes in NKCLs. We selected PRDM1 as the most likely tumor suppressor gene in NKCLs based on mutation and promoter methylation analysis on malignant NK-cell lines, which identified loss-of-function mutations and promoter CpG island methylation. Next, we detected the silencing of PRDM1 in 18 NKCL samples by performing deletion, mutation, and promoter methylation analysis. Unlike cell lines, we did not detect any deleterious mutations in NKCL cases; however, we observed frequent deletion and hypermethylation of PRDM1, which led to the loss of expression of PRDM1, as shown by q-RT-PCR on NK-cell lines and NKCL cases. Next, we observed a high IL2 concentration dependent cytotoxicity in NK-cell lines, detected by an increase in the rate of apoptosis, G2/M cell cycle arrest, and a negative selection pressure determined by the posttransduction elimination of GFP(+) NK-cells expressing exogenous PRDM1. In contrast, knockdown of PRDM1 with shRNA enhanced the growth of primary NK-cells, suggesting PRDM1 as a tumor suppressor gene in NKCLs. Finally, we observed down-regulation of MYC, TNFα and TNFβ in an NK-cell line transduced with PRDM1 suggesting PRDM1 may be transcriptionally repressing genes involved in NK-cell activation and homeostasis in NK-cells. In summary, we provided strong evidence that PRDM1 has a pivotal role in NK-cell homeostasis through a combination of genetic, epigenetic and biochemical approaches. Consequently, loss of function of PRDM1 may contribute to the pathogenesis of NK-cell malignancies, reconstitution of which may be used as a therapeutic target for NKCL patients in the future.

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