Deciphering the Oncogenic role of the transcription factor MAF in Plasma Cell Malignancies : Unveiling Novel Therapeutic Avenues in Multiple Myeloma.

Topic description

The Cell Therapy laboratory at the University Hospital of Amiens (CHU d’Amiens), France, is offering at the earliest opportunity a PhD student position initially limited to 3 years with the possibility of prolongation to study the role of the transcription factors cMAF and MAFB in malignant transformation of plasma cells.

About the Project

Multiple myeloma (MM) is a hematologic malignancy that develops via the transformation of normal plasma cells (PC) that expand in the bone marrow. MM is the second most common hematologic malignancy, with about , new diagnosed cases worldwide yearly and the global myeloma mortality amounted to , patients for the year . Despite the advent of novel therapies in recent years, MM remains an incurable disease that is the cause of about 20% of deaths from hematologic malignancy. Thus, there is a clinical need for more effective therapies against these malignancies, which requires a better understanding of the biology of this malignancy.

Towards this goal, it is important to understand the molecular processes underlying the oncogenic transformation of plasma cells into multiple myeloma. This knowledge will provide the scientific rationale and molecular basis for personalized medicine in the treatment of this devastating disease.

A classic genetic view of the development of MM is based on the acquisition of a series of stepwise genetic hits, where first event will immortalize the plasma cell (initiating cell or premalignant PC) and subsequent events will drive the progression through the precursor disease phase monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM) and active MM. Initiating genetic events are divided into non-hyperdiploid and hyperdiploid types that are almost mutually exclusive. The non-hyperdiploid group encompasses immunoglobulin heavy chain (IGH) locus translocations that juxtapose the IGH enhancers to another partner gene leading to it is overexpression (ex. CyclinD1, NSD2 and MAF). It remains completely unknown how the expression of these genes caused by IGH translocation modifies the biology and the molecular landscape of the initiating plasma cell and predispose to malignancy.

t(14;16) and t(14;20) are present in 5% and 1% of MM patients and results in overexpression of the transcription factor (TF) cMAF and MAFB, respectively. The t(14;16) translocation is associated with poor outcome. In addition, cMAF is overexpressed in more than 50% of primary MM cells and human myeloma cell lines. cMAF and MAFB are basic leucine zipper (bZIP) domain TF and members of the Activator Protein-1 (AP-1) TF family. cMAF dimers bind to specific DNA sequence called MAF- recognition element (MARE) interact with other TFs (such as BCL6), regulate gene expression and the differentiation of immune cells including T follicular helper cell and macrophage.

cMAF and MAFB are major players in MM development and progression. The knockdown or knockout of the cMAF and MAFB led to cell death of MM cell bearing the t(14;16) and t(14;20) translocations. These observations identify targeting of aberrant MAF expression as a treatment strategy. However, currently there are no therapies in the clinics that specifically target MAF. Therefore, understanding the role of cMAF and MAFB in malignant transformation of plasma cells is crucial in order to identify the precise, therapeutically targetable molecular components in the downstream pathways regulated by these transcription factors.

This project will establish the transcriptional programs and epigenetic mechanisms by which cMAF and MAFB overexpression drive MM initiation and identify new therapeutic strategies to target these mechanisms.

Techniques associated with this project

In addition to NGS (next generation sequencing), RNA-seq, CUT&Tag and ATAC-seq and bioinformatics, validation of the identified targets will involve a broad range of molecular and cell biology techniques, including cloning, PCR, gel electrophoresis, cell culture, mouse models, Western blotting, ELISA and flow cytometry.

Starting date

• 10-02

Funding category

Other public funding

Funding further details

Full funding is provided for the duration of the PhD by the University Hospital of Amiens (CHU d’Amiens).