| Abstract: |
Dysregulation of Janus kinase (JAK)-signal transducer and activator of transcription signaling is central to the pathogenesis of myelofibrosis (MF). JAK2 inhibitor therapy in MF patients results in a rapid reduction of the degree of splenomegaly, yet the mechanism underlying this effect remains unknown. The in vitro treatment of splenic and peripheral blood MF CD34+ cells with the JAK1/2/3 inhibitor, AZD1480, reduced the absolute number of CD34+, CD34+ CD90+, and CD34+ CXCR4+ cells as well as assayable hematopoietic progenitor cells (HPCs) irrespective of the JAK2 and calreticulin mutationalstatus.Furthermore, AZD1480treatment resultedinonlya modest reduction in the proportion of HPCs that were JAK2V617F+ or had achromosomalabnormality.To studytheeffect of the drugon MF stem cells (MF-SCs), splenicCD34+ cells were treated with AZD1480 and transplanted into immunodeficient mice. JAK2 inhibitor therapy did not affectthe degree of humancell chimerism or the proportion of malignant donor cells. These data indicate that JAK2 inhibitor treatment affects a subpopulation of MF-HPCs, while sparing another HPC subpopulation as well as MF-SCs. This pattern of activity might account for the reduction in spleen size observed with JAK2 inhibitor therapy as well as the rapid increase in spleen size observed frequently with its discontinuation. |
