APL · ANALYSIS OF PML/RARA ONCOGENIC COMPLEX IN ACUTE PROMYELOCYTIC LEUKEMIA
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-11-01 → 2012-10-31
- Финансиране от ЕС
- 166 146 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Острата промиелоцитна левкемия се причинява от неправилно сляване на протеините PML и RARα, което блокира развитието на клетките. Разбирането на този процес помага да се разбере как производни на витамин А премахват раковите клетки и постигат ремисия.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
ANALYSIS OF PML/RARA ONCOGENIC COMPLEX IN ACUTE PROMYELOCYTIC LEUKEMIA
Acute promyelocytic leukemia (APL) represents 10% to 15% of acute myeloid leukemias in adults. It is caused by a variety of chromosomal translocations into the retinoic acid receptor-α (RARα) gene. The t(15;17)(q22;q11.2) is the most common translocation and gives rise to promyelocytic leukemia PML- RARα fusion protein. PML-RARα is a transcriptional repressor that associates with a corepressor complex leading to transcriptional repression and thus, promyelocytic differentiation blockage. All-trans retinoic acid (RA), a derivative of vitamin A and the physiologic ligand of RARα, is able to elicit complete remission of APL and has been successfully used in clinical treatment of APL. Pharmacologic concentrations of RA trigger the dissociation of the correpressor complex and the recruitment of the coactivator complex, and lead to changes in gene expression, APL cell differentiation, but also degrade the fusion via proteasome by the retinoic acid‐bound RARα moiety of PML-RARα. It has been suggested that while transcriptional activation control differentiation, this may not be the primary basis for the therapeutic efficacy of RA in clearing APL-associated t(15;17). Indeed, only the leukemia initiating cells (LICs) clearance is responsible for the remission of mouse APL and high concentrations of RA are required for complete PML-RARα catabolism and full LIC clearance.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Acute promyelocytic leukemia (APL) appears to be primarily a monogenic disease characterised by a specific t(15 ;17) translocation that fuses the PML and the RARA gene to generate a PML/RAR fusion protein. PML/RARA is a transcriptional repressor, and RARA homo-dimerisation through the coiled coil of PML was believed to be the basis for repression via enhanced binding of co-repressors. Clinically, APL is exquisitely sensitive to retinoic acid (RA), arsenic trioxide and cAMP. This cardinal feature of the disease has been used to model its pathogenesis by analyzing the response to therapy of primary cells in vivo and ex vivo.Our aim is a further understanding the pathogenesis of acute promyelocytic leukemia, in particular the molecular bases of its response to RA, arsenic and cAMP. This will be essentially achieved through the analysis of the phenotype and transcriptome of cells or animals expressing PML/RARA mutants, by applying innovative approaches in cellular and molecular biology, such as purification of tagged proteins and ChIP.We propose two main objectives:- Partners identification of the oncogenic PML/RARA complex. Subsequently, we will analyse the functional domains of the complex and the changes in the complex induced by RA, arsenic and cAMP.- Analysis of PML/RARA-dependent target gene repression. We will compare between different PML/RARA mutants in respect to the chromatin or DNA status of the target gene promoters.This project addresses new therapeutic targets in APL and other types of cancer where RARA is implicated. It is a multidisciplinary project that involves a highly valuable education for the candidate in new scientific aspects related to her research field.
Оригинален текст от CORDIS (на английски).
Участници
- Université Paris Diderot-Paris 7 · ParisКоординаторФранция
Връзки
Данни: CORDIS, © Европейски съюз