Have you heard of the so-called “leukemic stem cell”? These cells reside within bone marrow in a “malignant niche” which promotes survival and proliferation. Bone marrow contains hematopoietic stem cells which give a body’s blood cells an infinite life line. That is a good thing until the hematopoietic stem cell undergoes a genetic mutation by recombining chromosome 9 and 22.
This incorrectly assembled chromosome is called the Philadelphia chromosome and leads to chronic myeloid leukemia. Scientists from the Max Planck Institute of Biochemistry in Martinsried, Germany, have found a new way to make these cells vulnerable by specifically dislodging these cells from their niches.
To target the malignant niche the scientists focused on the integrins that attach themselves to the “scaffolding”of the proteins or, extracellular matrix. In the “leukemic stem cell”, the activity of the integrins is promoted by an intracellular protein called Kindlin.
Peter Krenn, first author of the study, explains: “The isoform Kindlin-3 is only used by blood cells. If mice harbor leukemic stem cells that lack Kindlin-3, they do not develop leukemia. Without Kindlin-3 and active integrins, the leukemic 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 leukemic stem cells lack the urgently needed support, which they usually receive from the niche, and die.”
The new therapeutic approach finds that these diseased stem cells express a protein called CTLA-4 on their surface, which is absent from healthy blood stem cells. This allows researchers to distinguish the two easily and use the CTLA-4 as a shuttle to deliver the Kindlin-3 destroying compound. The stem cell then without Kindlin-3 is expelled from the bone marrow and the leukemia loses its fuel.
Peter Krenn summarizes: “In our current study we have developed a new therapeutic approach to treat chronic myeloid leukemia in mice. However, the principle of the therapy is universally valid. The inhibited Kindlin-3 production and consequent loss of integrin function prevents the cancer cells from being able to adhere and settle in tumor-promoting niches. I assume that this method will also prevent the cancer cells of other types of leukemia from settling and that these diseases could thus become much more treatable.”
A hallmark of all cancers is the capacity for unlimited self-renewal, which is also a defining characteristic of normal stem cells. Being able to identify Leukemic isoforms for each type of leukemia is a daunting task but a critical step in understanding effective treatments. “Leukemic stem cell” identification and purification will hopefully lead to powerful therapeutic tools and revolutionary research for stem cells.