Syk tyrosine kinase inhibitors (TKIs), such as imatinib, may be effective in treating sickle cell disease (SCD), according to research published in the British Journal of Haematology.
Currently, the mechanisms of SCD symptoms are still a matter of debate. While most symptoms are associated with occlusion of the microvasculature, an increasing number of researchers suggest that some sequelae are caused by erythrocyte membrane weakening, which in turn leads to microparticle discharge and free sickle hemoglobin.
This process may be linked with oxidative stress and inhibition of red blood cell tyrosine phosphatases that normally prevent constitutive Band 3 tyrosine phosphorylation. Panae Noomuna, MS, from Purdue University in West Lafayette, Indiana, and associates explored the role of Band 3 tyrosine phosphorylation and associated membrane weakening in SCD symptom development.
The researchers first established that sickle cells are distinguishable by increased tyrosine phosphorylation of Band 3, membrane weakening, and microparticle/cell-free hemoglobin release by evaluating samples from 48 pediatric patients who had not yet undergone transfusion (mean age, 9.3 years). They found that cell-free hemoglobin was twice as concentrated in plasma from patient samples vs healthy volunteers.
The researchers next evaluated the effects of Syk TKIs in cellular models and found that these treatments block Band 3 tyrosine phosphorylation, prevent free hemoglobin release, inhibit membrane-derived microparticle discharge, increase sickle cell deformability, reduce sickle cell adhesion to endothelial cells, and improve sickle cell flow in microcapillaries.
Noting that imatinib, a Syk TKI used to treat chronic myeloid leukemia (CML), has anecdotally been associated with treating SCD symptoms in patients with CML, the authors concluded that “a well-designed short term clinical evaluation of imatinib in a more mature population could provide a proof-of-concept test which would inform whether a search for a more selective inhibitor of Band 3 tyrosine phosphorylation might be worthwhile.”
Noomuna P, Risinger M, Zhou S, et al. Inhibition of Band 3 tyrosine phosphorylation: a new mechanism for treatment of sickle cell disease [published online April 28, 2020]. Br J Haematol. doi: 10.1111/bjh.16671