A New Target Linked with Several Aggressive Forms of Blood Tumour

Reza Roozitalab Posted in General News, Publications 23 October 2017

Lamin B1 - a potential target for follicular lymphoma and Chronic lymphocytic leukaemia

Manipulating levels of the protein Lamin B1 may one day prove an effective treatment option for patients with lymphomas and chronic lymphocytic leukaemia (CLL), according to research at the BCI.

Funded by the Kay Kendall Leukemia Fund, the findings of the research published in Leukemia describe Lamin B1 (LMNB1) as a negative epigenetic regulator of ‘somatic hypermutation’ in normal B-cells and a ‘mutational gatekeeper’ guarding cells against further genetic abnormalities that drive cancer.

A Braun

By monitoring the levels of Lamin B1 over time in patient biopsies, researchers saw a continuous and sequential drop as the disease transformed into an even more aggressive form.

With this understanding, Lamin B1 could be used as a biomarker to diagnose and identify those patients at risk of progression, particularly those with extremely aggressive forms of follicular lymphoma (FL) for whom no such measures currently exist.

Andrejs Braun, lead investigator and group leader at the BCI said: "We were quite surprised how strongly and generally this mechanism translated into the biology of various B-cell malignancies. Follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukaemia are to mention a few."


B-cells are an integral part of our immune response.

They recognise a foreign body and divide rapidly to produce antibodies against the "invader" to allow other immune cells to find and destroy it

A key process for B-cells is called Somatic hypermutation (SHM), which allows them to diversify, adapt and personalise these antibodies against all new threats.

Here, the protein Lamin B1 is described as a novel epigenetic regulator of SHM. Due to its location inside the nuclear membrane and proximity to the cell’s genetic material, it sits closely bound to a section of DNA to suppress SHM in resting B-cells - when it is not required.

Epigenetic changes are a hallmark of cancer that regulate the expression of genes and proteins without changing the underlying DNA code.

The researchers saw that whilst a temporary drop in Lamin B1 was necessary to allow normal activated B-cells to undergo SHM, in cancer cells, these levels never recovered.

In chronic lymphocytic leukaemia, the data indicated a strong association between low Lamin B1 expression and an unfavourable prognosis linked with a greater number of chromosomal abnormalities.

The team, therefore, hypothesise that a drop in Lamin B1 permits greater opportunities for CLL cells to acquire the very mutations that allow them to thrive.

In the future, drugs inhibiting the degradation of Lamin B1 may provide a more efficient means of therapy, compared with conventional chemotherapies and their associated toxicities.

 

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