Potential Role of WW Domain Containing Oxidoreductase Gene in Myeloproliferative Neoplasms

الموضوعات

علوم تطبيقية وتكنولوجية

الملخص

Myeloproliferative Neoplasms (MPN) represent a group of clonal hematologic disorders characterized by aberrant proliferation of myeloid cells in the bone marrow. One class of MPNs is classical Philadelphia-negative MPN, which is caused by several driver mutations, with the most common one being JAK2V617F mutation, leading to constitutive activation of the JAK-STAT pathway. The tumor suppressor WW domain-containing oxidoreductase (WWOX), located in one of the most active fragile sites in the human genome (FRA16D), is known to play a significant role in cancer suppression. Alterations in WWOX, especially null mutations resulting in the loss of the protein, along with epigenetic modifications involving the methylation of the WWOX gene's CpG island, have been identified in various types of cancer. However, WWOX alteration and its direct contribution to MPN development and progression remain largely unknown. This study aims to investigate the role of the WWOX gene in JAK2V617F mutation and Philadelphia-negative myeloproliferative neoplasms. Our findings reveal diverse WWOX protein expression patterns across MPN cell lines, indicating potential subtype-specific alterations, with detectable WWOX expression in UKE1 and HEL cell lines exhibiting varying levels, while notably absent in the SET2 cell line. This heterogeneity in WWOX expression underscores the complexity of MPN subtypes. To investigate the role of WWOX in this MPN, we manipulated its expression in SET2 and UKE1 cell lines using both overexpression and CRISPR-knockout techniques respectively. We then employed a combination of Sanger sequencing, RT-PCR, western blotting, and proliferation assays to show our findings. Surprisingly, WWOX overexpression led to elevated levels of phospho-ERK and phospho-STAT3 (Y705), along with a reduction in cell viability and an increase in the expression of BCL2 proteins. Conversely, WWOX knockout resulted in reduced levels of phospho-ERK, challenging our initial expectations regarding phospho-ERK and phospho-STAT3vi (Y705). These findings suggest a potential tumor suppressor role for both WWOX, STAT3 and ERK in MPNs. Further research is needed to elucidate the underlying molecular mechanisms of these tumor suppressor functions. Importantly, understanding the complex interplay between WWOX, JAK-STAT signaling, and MPN development could have significant implications for the diagnosis and treatment of these disorders.

روابط وملفات

التعريف والنوع

رقم الوثيقة

03a15c6a-834e-4363-8508-b79ff34194ff

رقم العقد

0

نوع الوسائط

Crawler

نوع المحتوى

الرسائل العلمية

صيغة المصدر

رسائل ماجيستير

نوع الملف

pdf text

أسماء الملفات

2442185_1.pdf

بيانات النشر

ألقاب المؤلفين

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اللغة

English

المصدر والدورية

اسم المصدر

Potential Role of WW Domain Containing Oxidoreductase Gene in Myeloproliferative Neoplasms

المحتوى والصفحات

عدد الصفحات

0

كلمات الباحثين

molecular genetics,genetics toxicology,cancer,myeloied cells

إشراف وإعداد

الإشراف

زيدون صالح

الإعداد

خلود صالح ابو صالح

الاقتباسات الببليوغرافية