Image courtesy of UCSD
New discoveries concerning a well-known tumor suppressor protein could help advance the diagnosis and treatment of chronic myeloid leukemia (CML), according to researchers.
They found that levels of the protein, BRCA1, are significantly decreased in advanced phases of CML, the expression of BCR-ABL1 correlates with decreased levels of BRCA1, and this downregulation of BRCA1 is caused by the inhibition of BRCA1 messenger RNA (mRNA) translation.
These discoveries explain the mechanism that supports CML development and uncover its weakness, the investigators said. They reported their findings in Cell Cycle.
“Our data demonstrated that BRCA1 synthesis is diminished in [the] advanced stage[s] of CML,” said study author Paulina Podszywałow-Bartnicka, PhD, of the Nencki Institute in Warsaw, Poland.
“The gene coding for BRCA1 protein is not mutated. However, BRCA1 mRNA, which is necessary for the protein production, is aggregated and stored in protein complexes [and], thus, not available for the protein synthesis.”
To gain more insight into this phenomenon, the investigators looked at 2 mRNA-binding proteins, HuR and TIAR. They found that BCR-ABL1 promoted cytosolic localization of TIAR and HuR, the proteins’ binding to BRCA1 mRNA, and formation of the TIAR-HuR complex.
The researchers also found that HuR positively regulated BRCA1 mRNA stability and translation, while TIAR negatively regulated BRCA1 translation.
TIAR-dependent downregulation of BRCA1 was a result of endoplasmic reticulum stress, which is activated in BCR-ABL1 expressing cells. And experiments showed that silencing TIAR in CML cells elevated BRCA1 levels.
This suggests that TIAR-mediated repression of BRCA1 mRNA translation is responsible for the downregulation of BRCA1 observed in BCR-ABL1-positive leukemia cells.
The investigators said this research indicates that BRCA1 deficiency, which supports CML, can be also used as a weapon against the disease.
“When a cell has damaged one signaling pathway or one gene, it may function properly due to alternative pathways . . . ,” explained study author Tomasz Skorski, MD, PhD, of Temple University School of Medicine in Philadelphia, Pennsylvania.
“Only when this alternative pathway is inhibited [do cells] lose the ability to survive. As we know that one of the [DNA double-strand break] repair pathways which depend on BRCA1 is blocked in leukemia cells, we can try to find the alternative, parallel pathway and inhibit it as well.”
This will induce apoptosis via synthetic lethality, but only in leukemia cells, because healthy cells still have functional BRCA1-dependent signaling. Dr Skorski noted that therapies based on BRCA1 deficiency are currently under investigation in clinical trials.
