Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation

Michelle C. Krutein, Matthew R. Hart, Donovan J. Anderson, Jasmin Jeffery, Andriana G. Kotini, Jin Dai, Sylvia Chien, Michaela DelPriore, Sara Borst, Jean Ann Maguire, Deborah L. French, Paul Gadue, Eirini P. Papapetrou, Siobán B. Keel, Pamela S. Becker, Marshall S. Horwitz

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


RUNX1 familial platelet disorder (RUNX1-FPD) is an autosomal dominant disorder caused by a monoallelic mutation of RUNX1, initially resulting in approximately half-normal RUNX1 activity. Clinical features include thrombocytopenia, platelet functional defects, and a predisposition to leukemia. RUNX1 is rapidly degraded through the ubiquitin-proteasome pathway. Moreover, it may autoregulate its expression. A predicted kinetic property of autoregulatory circuits is that transient perturbations of steady-state levels result in continued maintenance of expression at adjusted levels, even after inhibitors of degradation or inducers of transcription are withdrawn, suggesting that transient inhibition of RUNX1 degradation may have prolonged effects. We hypothesized that pharmacological inhibition of RUNX1 protein degradation could normalize RUNX1 protein levels, restore the number of platelets and their function, and potentially delay or prevent malignant transformation. In this study, we evaluated cell lines, induced pluripotent stem cells derived from patients with RUNX1-FPD, RUNX1-FPD primary bone marrow cells, and acute myeloid leukemia blood cells from patients with RUNX1 mutations. The results showed that, in some circumstances, transient expression of exogenous RUNX1 or inhibition of steps leading to RUNX1 ubiquitylation and proteasomal degradation restored RUNX1 levels, thereby advancing megakaryocytic differentiation in vitro. Thus, drugs retarding RUNX1 proteolytic degradation may represent a therapeutic avenue for treating bleeding complications and preventing leukemia in RUNX1-FPD.

Original languageEnglish
Pages (from-to)687-699
Number of pages13
JournalBlood advances
Issue number3
StatePublished - 9 Feb 2021


Dive into the research topics of 'Restoring RUNX1 deficiency in RUNX1 familial platelet disorder by inhibiting its degradation'. Together they form a unique fingerprint.

Cite this