Genomic translocations, super-enhancer hijacking and oncogene activation: from mechanism to therapy
Lead Research Organisation:
Newcastle University
Department Name: Translational and Clinical Res Institute
Abstract
Background
Haematopoiesis is a developmental process which culminates in the formation of all the blood cells required in our immune system. Errors in this process leads to the accumulation of cells held at a specific stage of differentiation, resulting in the development of haematological malignancies.
Genomic translocations are a hallmark of cancer. Their identification has led to improvements in diagnosis and outcome in haematological malignancies. We are particularly interested in leukaemias and lymphomas resulting from translocations in the immunoglobulin (Ig; antibody) locus in B lymphocytes. Normal rearrangement of Ig gene loci and their super-enhancers is needed to generate the antibody repertoire, but these super-enhancers can be aberrantly rearranged and "hijacked" by oncogenes. However, our understanding of this genomic information is very limited and therapeutic strategies exploiting this data are yet to be developed.
Over 70 genes are translocated to the Ig loci and overexpressed as a result of the rearrangement, but this is not a random process. Recurrent translocations imply a common mechanism that supports developmental stage-specific, long-range interactions between particular promoters and enhancers. A strong candidate mechanism would be shared transcriptional regulatory proteins (TRPs) that might bind regulatory regions at each locus, favouring the translocation.
Objectives
This project will develop and apply computational methods together with complementary laboratory experiments to identify key TRPs in normal and malignant human B-cell development.
Haematopoiesis is a developmental process which culminates in the formation of all the blood cells required in our immune system. Errors in this process leads to the accumulation of cells held at a specific stage of differentiation, resulting in the development of haematological malignancies.
Genomic translocations are a hallmark of cancer. Their identification has led to improvements in diagnosis and outcome in haematological malignancies. We are particularly interested in leukaemias and lymphomas resulting from translocations in the immunoglobulin (Ig; antibody) locus in B lymphocytes. Normal rearrangement of Ig gene loci and their super-enhancers is needed to generate the antibody repertoire, but these super-enhancers can be aberrantly rearranged and "hijacked" by oncogenes. However, our understanding of this genomic information is very limited and therapeutic strategies exploiting this data are yet to be developed.
Over 70 genes are translocated to the Ig loci and overexpressed as a result of the rearrangement, but this is not a random process. Recurrent translocations imply a common mechanism that supports developmental stage-specific, long-range interactions between particular promoters and enhancers. A strong candidate mechanism would be shared transcriptional regulatory proteins (TRPs) that might bind regulatory regions at each locus, favouring the translocation.
Objectives
This project will develop and apply computational methods together with complementary laboratory experiments to identify key TRPs in normal and malignant human B-cell development.
Organisations
People |
ORCID iD |
| Daniel Kent (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013840/1 | 30/09/2016 | 29/09/2025 | |||
| 2306763 | Studentship | MR/N013840/1 | 30/09/2019 | 30/07/2023 | Daniel Kent |
| NE/W50306X/1 | 31/03/2021 | 30/03/2022 | |||
| 2306763 | Studentship | NE/W50306X/1 | 30/09/2019 | 30/07/2023 | Daniel Kent |