02 November 2020

A new method could prevent chronic myeloid leukaemia (CML) stem cells from being retained in the bone marrow and other areas which support tumour growth, German researchers have reported.

The team, from the Max Planck Institute of Biochemistry in Martinsried, used an RNA molecule complex to disrupt the “tumour-promoting and protecting niche within the bone marrow”.

It selectively dislodged these CML stem cells from their niches, they report in the journal PNAS recently. Leukaemic stem cells use an intracellular protein called Kindlin-3 to attach to the extracellular matrix and stay within their protective niche in the bone marrow.

Researcher Dr Peter Krenn, explains: “The isoform Kindlin-3 is only used by blood cells. If mice harbour leukaemic stem cells that lack Kindlin-3, they do not develop leukaemia.

“Without Kindlin-3 and active integrins, the leukaemic stem cells cannot attach themselves to their niche environment and are released from the bone marrow into the blood. Since they cannot home elsewhere either, they remain in the blood. There the leukaemic stem cells lack the urgently needed support, which they usually receive from the niche, and die.”

Since Kindlin-3 is also used by normal haematopoietic stem cells, the team had to come up with a technique to dislodge the leukaemic stem cells only. They found that the protein CTLA‑4 is produced only on leukaemic stem cells and not on normal stem cells. To exploit this, the team designed an RNA molecule which binds to CTLA‑4, which is attached to a genetic message which stops the production of Kindlin-3. In experiments with mouse models of CML, they showed that the therapeutic RNA molecule stopped the leukaemia stem cells from producing Kindlin-3, leading to them being ‘flushed’ from the bone marrow, and extending the survival of the mice.

“In our current study we have developed a new therapeutic approach to treat chronic myeloid leukaemia in mice,” concluded Dr Krenn. “However, the principle of the therapy is universally valid. I assume that this method will also prevent the cancer cells of other types of leukaemia from settling and that these diseases could thus become much more treatable”.


Source: Krenn PW, Koschmieder S, Fässler R. (2020) “Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches.” PNAS, doi: 10.1073/pnas.2009078117

 

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