LncRNAs: Novel therapeutic targets to treat Multiple Myeloma with RNA-based therapies

• Autores: Ane Amundarain
• Directores de la Tesis: Felipe Prósper Cardoso (dir. tes.), Xabier Aguirre Ena (dir. tes.)
• Lectura: En la Universidad de Navarra ( España ) en 2023
• Idioma: inglés
• Número de páginas: 217
• Materias:
  • Ciencias de la vida
    • Biología humana
      • Genética humana
  • Ciencias médicas
    • Ciencias clínicas
      • Genética clínica
    • Medicina interna
      • Hematología
• Enlaces
  • Tesis en acceso abierto en: Dadun
• Resumen

  • Insights into B-cell development and plasma cell biology are essential for understanding the disease known as Multiple Myeloma (MM). The differentiation from a precursor cell into a terminally differentiated, antibody producing plasma cell (PC) is a complex and tightly regulated process, guided by maturation-specific transcriptional programs and external cues such as cytokines present in the bone marrow and secondary lymphoid organs1,2. B lymphocytes develop in the bone marrow (BM) from precursor hematopoietic stem cells (HSC) (Figure 1A), which are the origin of all blood cells3 HSCs differentiate into common lymphoid progenitors that commit to the B-cell lineage due to the expression of lineage-specific transcription factors such as EBF1, PAX5 and E2A3,4. Early BM-dependent stages of B-cell development are structured along the functional rearrangement of immunoglobulin genes, where heavy chain (H- chain) VH-DH-JH segments and light-chain (L-chain) VL-JL segments are rearranged. Finally, early B-cell development is finalized when immature B-cells expressing IgM molecules leave the BM and migrate to secondary lymphoid organs where they further differentiate into Naïve (NBC), follicular or marginal zone B cells1,5. Naïve B cells circulate through peripheral blood and the lymphatic system and enter secondary lymphoid tissues where they can be activated upon exogenous antigen encountering and T cell interaction1,6. Activated B cells can either develop directly into extrafollicular short-lived plasma cells or can mature into germinal center (GC) precursor B-cells6,7. GC microenvironments are formed by proliferating B cells in the follicles of peripheral lymphoid tissues, and are the main site of antibody diversification and affinity maturation (Figure 1B) 6,7. In GCs, B cells are subjected to repeated rounds of somatic hypermutation (SHM) and affinity selection, together with the class-switch recombination (CSR) of heavy chain isotypes, resulting in progressive increase of antibody affinity during immune responses6,7. In brief, SHM is a process that modifies the immunoglobulin variable region (IgV) of the rearranged antibody genes during an immune response, creating a repertoire of diverse B cell receptors whose affinity is “tested” and the best ones are selected. On the other hand, CSR is an irreversible somatic recombination mechanism by which B cells change their immunoglobulin heavy chain expression to gain distinct effector functions6 Finally, clonally selected high-affinity antibody producing GC B cells are terminally differentiated into memory B cells or PCs6,7. Mature PCs are specialized in the production and secretion of high amounts of protective high-affinity antibodies, and they migrate to the BM to turn into long-lived PCs and become central elements of the adaptive immune system1,4. In contrast, the mechanisms that drive memory B cell development are less clear, but they comprise a group of pathogen-experienced cells which are rapidly reactivated upon re- infection4,8.