Updated: Nov 10, 2020
Research identifies a new way to target leukaemia cells
Dislodgement of leukaemia stem cells from a tumour-promoting niche within bone marrow. is a recent discovery by Researchers to make leukaemia cells vulnerable.
Blood cells have a short life span. They are lost during bleeding or may be consumed during infections as a result they must be replaced constantly. Haematopoietic stem cells located in the bone marrow are responsible for this replacement.
Chronic myeloid leukaemia causes genetic mutation of haematopoietic stem cell by recombining chromosome 9 and 22. This fuses unrelated and unconnected gene building blocks. This incorrectly assembled chromosome is called the Philadelphia chromosome and carries the instructions for the BCR-ABL oncogene. This causes division of leukaemic stem cells at the expense of healthy blood stem cells.
A malignant niche is created by the leukaemic stem cell, an environment that ensures survival and proliferation. In other to ensure sustenance in this niche the leukaemic stem cell attaches itself to a scaffold of extracellular proteins and to other neighboring cells with the aid of integrins. The activity of the integrins is within the leukaemic stem cell is facilitated by Kindlin an intracellular protein.
Leukaemic stem cells that lack Kindlin-3 do not cause leukaemia. In the absence of Kindlin-3 and integrins, leukaemic stem cells cannot attach to the niche environment, this causes their release from the bone marrow into the blood. As a result of these release, they die due to lack of support from the niche.
The expression of the protein CTLA-4 on the surface of leukaemic stem cells allowed researchers to differentiate between a leukaemic blood stem cell from a healthy blood stem cell. This CTLA-4 recptor served as a conveyor to deliver a Kindlin-3 destroying compound into leukaemic stem cells.
CTLA-4 exists briefly on the cell surface before being recycled into the cell and then back again to the cell surface. This enabled the successful introduction of a Kindlin-3 degrading siRNA into the cell by coupling it to a CTLA-4-binding RNA sequence, which is called aptamer. A leukaemic stem cell not containing Kindlin-3 is flushed out of the bone marrow and the leukaemia loses its origin and runs out of fuel.
A new therapeutic approach has been developed for the treatment of chronic myeloid leukaemia in mice. The principle of the therapy is valid globally. The inhibited Kindlin-3 production and consequent loss of integrin function prevents cancer cells from adherence and settlement in tumour promoting niches, this could also prevent cancer cells of other types of leukaemia from settling.