Restoring RUNX1 Levels in FPD/AML
Familial platelet disorder with predisposition to acute myeloid leukemia (FPD/AML) is caused by inheritance of a nonfunctioning copy of the RUNX1 gene from just one parent. The other copy of the RUNX1 gene, inherited from the unaffected parent, is normal. Therefore, at least in the early stages, disease is caused by approximately half-normal levels of RUNX1.
We will test two strategies for returning overall levels of functional RUNX1 protein to normal in order to restore platelet numbers, function and prevent transition from pre-leukemia to leukemia. First, we note that RUNX1 protein is short-lived and rapidly degraded in a controlled manner through a series of enzymatic steps. We propose to test whether drugs inhibiting the steps regulating the degradation of normal RUNX1 protein produced from the copy of the gene inherited from the unaffected parent can boost total RUNX1 levels back into the usual physiologic range. Second, RUNX1 protein activates its own expression through a positive feedback loop, which suggests that even temporarily increasing RUNX1 levels can lead to a larger, more stable, longer term increase in overall RUNX1 protein levels.
The proposed experiments will be performed in FPD/AML patient-derived induced pluripotent stem cells (iPSC) we previously helped develop. If successful, these experiments will set the stage for clinical drug trials or even new forms of therapy in which bone marrow cells are treated in a dish and then returned to the body. The overall goal is to correct platelet abnormalities and prevent leukemia occurrence in FPD/AML.