Get out of your comfort zone!
Leukemia often arises from so–called leukemic stem cells, which are located in the bone marrow in a tumor niche - an environment of cells that contribute to the progression and resistance of the tumor. Scientists from the Max Planck Institute of Biochemistry in Martinsried, Germany, have found a new way to displace atypical cells from their niches and thus make them vulnerable.
Since blood cells have a limited life span, are lost during bleeding or are consumed during infections, their number must be constantly replenished. This supply is provided by hematopoietic stem cells of the bone marrow, which can develop into blood cells of any type.
In chronic myeloid leukemia, hematopoietic stem cells undergo mutation – recombination of chromosomes 9 and 22. As a result, blocks of genes merge, which normally would not be in contact with each other. An improperly assembled chromosome is called the Philadelphia chromosome, it contains a guide to the construction of the BCR-ABL oncogene. This causes leukemic stem cells to divide at the expense of healthy blood stem cells.
No kindlin-3 – no leukemia
A leukemic stem cell creates an environment called a malignant niche that ensures its survival and reproduction. To stay in this tumor niche, the leukemic stem cell uses transmembrane integrin receptors, which allow it to attach to extracellular proteins and neighboring cells. In leukemic stem cells, the intracellular protein kindlin contributes to the activity and function of integrins.
The kindlin-3 isoform is used only by blood cells. If mice do not have kindlin-3 in leukemic stem cells, they do not develop leukemia. Without this protein and active integrins, leukemic stem cells cannot gain a foothold in the niche and are released from the bone marrow into the blood. Since they also cannot gain a foothold elsewhere, they remain in the blood and quickly die without the support they usually receive from the niche.
New treatment: kindlin-3 and CTLA-4
When it became known that leukemic stem cells express CTLA-4 protein on their surface, which is absent in healthy cells, researchers were able to distinguish leukemic blood stem cells from healthy blood stem cells. CTLA-4 briefly enters the cell surface, then quickly returns back, and then again to the cell surface. This made it possible to use it as a carrier for delivering CTLA-4 binding miRNA to leukemic stem cells. A leukemic stem cell without kindlin-3 is washed out of the bone marrow, leukemia loses the first link in the pathogenetic chain and does not develop.
In the current study, a new therapeutic approach was applied to the treatment of chronic myeloid leukemia in mice. However, the principle of therapy is universal. Inhibition of kindlin-3 production and, as a consequence, loss of integrin function prevents cancer.
Article by P.W.Krenn et al. Kindlin-3 loss curbs chronic myeloid leukemia in mice by mobilizing leukemic stem cells from protective bone marrow niches is published in the journal PNAS.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of Max Planck Gesellschaft: New therapeutic approach against leukemia.