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

Abstract

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maintenance of expression at adjusted levels, even after inhibitors of degradation or inducers of transcription are withdrawn, suggesting that transient inhibition of RUNX1 degradation may have prolonged effects.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.

An Empirical Analysis of the Role of Piano Performance in Alleviating Psychological Trauma in People with Psychological Isolation Disorder

“…Research on music therapy began in the United States in the early 20th century, with music therapy being used early on for patients with significant physical and mental impairments and gradually expanding after World War II to include treatment for children and adults with special needs affected by intellectual, physical health, mental health, and participation in social activities (such as soldiers in World War II) [6]. Some American researchers have described music therapy as a systematic intervention process in which the music therapist interacts with the patient in different types of musical experiences to achieve therapeutic goals.…”

B-cell acute lymphoblastic leukemia in patients with germline RUNX1 mutations

“…17 NF-E2 and RUNX1 co-occupy cis elements in megakaryocytes for critical activity of genes in thrombopoiesis. 18 It is not known whether RUNX1 deficiency potentiates stress thrombopoiesis, whether stress thrombopoiesis overcomes RUNX1-FPD-related thrombocytopenia, or whether certain cytotoxic drugs enhance the activity or the abundance of the wild-type RUNX1 protein, similar to proteosome inhibitors, 19 temporarily correcting the thrombocytopenia.…”

Molecular Basis of Hematological Disease Caused by Inherited or Acquired RUNX1 Mutations

“…This task requires a clear understanding of the mechanism of why this predisposition exists and how transformation takes place. Krutein et al [123] recently suggested inhibition of RUNX1 degradation as a potential therapy, which they found to be partially effective in an iPSC model containing RUNX1, with a splicing defect resulting in a frameshift and early termination. However, this study also did not determine whether this mutation produced a protein-any protein produced would be truncated without the transactivation domain [123].…”

“…Krutein et al [123] recently suggested inhibition of RUNX1 degradation as a potential therapy, which they found to be partially effective in an iPSC model containing RUNX1, with a splicing defect resulting in a frameshift and early termination. However, this study also did not determine whether this mutation produced a protein-any protein produced would be truncated without the transactivation domain [123]. Similarly, overexpression of wild-type RUNX1 partially rescues erythroid and megakaryocyte differentiation defects caused by point mutation in the RHD [124].…”