IRE1 alpha may be causing abnormal loss of p53 at post transcriptional level in chronic myeloid leukemia

TL;DR

This paper suggests that IRE1 alpha may cause abnormal p53 mRNA degradation in CML, contributing to disease progression and drug resistance, and proposes targeting IRE1 alpha as a potential therapy.

Contribution

It introduces a novel hypothesis that IRE1 alpha influences p53 mRNA stability in CML and proposes inhibiting IRE1 alpha as a new therapeutic approach.

Findings

IRE1 alpha may cause p53 mRNA degradation in CML

Inhibition of IRE1 alpha could restore p53 function

Potential for new therapies targeting IRE1 alpha

Abstract

Current treatment strategy for chronic myeloid leukemia (CML) mainly includes inhibition of tyrosine kinase activity, which has dramatically improved the prognosis of the disease but without cure. In addition some patients may become drug resistant. Thus there is still the need for other therapies to avoid resistance and if possible to cure the disease. Loss of p53 is known to play an important role in the disease progression of CML and causes drug resistance. Here I propose that in CML, inositol requiring enzyme 1 alpha (IRE1 alpha) may cause abnormal degradation of p53 mRNA resulting in inhibition of apoptosis in leukemic clonal cells, which has not been elucidated before. Hence, I propose that inhibition of endoribonuclease activity of IRE1 alpha with small molecule inhibitors may provide a novel strategy to enhance p53 function in CML leukemic clones to overcome the limitations of current treatment regimens.