Targeting of signaling pathways in leukemia and conditioning for bone marrow transplant

by Alexey Bersenev on November 10, 2009 · 0 comments

in niche, quiescence

Recently new and exciting techniques were developed for safe (non-myeloablative) treatment, which allow permissive donor hematopoietic stem cell (HSC) engraftment. For example, depletion of host HSC by administration anti-cKit antibody was permissive for robust engraftment of donor bone marrow cells without irradiation-based conditioning. Targeting of surface molecules on donor’s marrow cells is currently jumping to the clinic. This technique allows us to make transplant settings much safer, more efficient and more affordable.

The whole point of efficient conditioning used in bone marrow transplant clinic is making “enough free niche spaces” for newly arrived donor stem cells or in other words – increase engraftment. Targeting selective surface markers or signaling pathways turning on in HSC will provide safe, non-toxic and efficient engraftment. The only thing that bothers me (and obviously not only me) is that pretty much the same approaches were proposed for efficient elemination of leukemia-initiating cells. Fresh example – targeting of STAT-5 signaling pathway.

This pathway is frequently activated in many leukemias and proposed to be a good “druggable target”. It happens that the same pathway is responsible for keeping normal HSC quiescent – some kind of “stemness-keeper”. So when we give an anti-STAT-5 drug to the patient we will kill his/her normal quiescent HSC, which are making all the blood in the body. We are really stuck with this problem. Virtually all selective anti-leukemic drugs are not really selective. Will they leave enough normal HSC to keep suffering patient survive? Will they kill all of leukemic stem cells with a guarantee of no relapse? Any ideas how to solve this puzzle?

I’d like to come back to conditioning now. Even if targeting of pathways is not going to work very nicely for leukemia, we can try to apply this technique for “making more niche available” in bone marrow transplantation. The first evidence for using inhibition of signaling pathways was recently demonstrated – good engraftment of donor’s HSC without irradiation-based conditioning. So, anti-STAT5 drugs can take the place in the line of “surface-targeting buddies” – cKit, MPL, CD45 ect. Can’t wait for clinical trials using this or similar approaches.

Connotea tags: conditioning / STAT-5 / quiescence / c-kit / MPL / niche

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